CD3/T cell receptor complex disorders causing immunodeficiency

INTRODUCTION — The T cell receptor (TCR) complex and its associated molecules are essential for T cell ontogeny and proper function of mature T cells. Deficiency in one of these components may result in major T cell deficiency or dysfunction. The clinical presentation of these defects varies widely, depending upon the severity of the genotypic abnormality. All of these immunodeficiencies are rare.

A brief review of TCR biology is first presented in this topic review to better understand disorders of the TCR complex that are associated with immunodeficiency. Detailed discussions of these topics are presented separately. Immunodeficiencies that result from defects in individual TCR complex components are then reviewed. Idiopathic cluster of differentiation 4 (CD4) lymphopenia is discussed separately. (See "The adaptive cellular immune response: T cells and cytokines" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation' and "Normal B and T lymphocyte development" and "Antigen-presenting cells" and "Major histocompatibility complex (MHC) structure and function" and "Human leukocyte antigens (HLA): A roadmap" and "Idiopathic CD4+ lymphocytopenia".)

OVERVIEW OF T CELL RECEPTOR BIOLOGY — The TCR is a heterodimer, with approximately 95 percent of peripheral blood T cells possessing an alpha and a beta chain (TCR alpha-beta or TCR2) and the remainder a gamma and a delta chain (TCR gamma-delta or TCR1) [1]. TCR gamma-delta is more abundant in skin and intraepithelial lymphocytes. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

TCR chains belong structurally to the immunoglobulin gene superfamily. Thus, TCR genes undergo recombination of the variable, diversity, and joining segments, called V(D)J recombination. This event is dependent upon the function of recombinase-activating genes 1 and 2 (RAG1 and RAG2) [1,2]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

A protein must first be processed by antigen-presenting cells (APCs) for T cells to recognize a specific antigen. APCs degrade the target antigen into several peptides. These peptides are subsequently presented on the cell surface in the groove formed by either a class I or II major histocompatibility complex (MHC I or MHC II) molecule. The human leukocyte antigen (HLA) system is synonymous with the human MHC. (See "Antigen-presenting cells" and "Major histocompatibility complex (MHC) structure and function" and "Human leukocyte antigens (HLA): A roadmap".)

Antigens processed for presentation in the context of MHC I must be transported to the endoplasmic reticulum (ER), where MHC I is assembled. Two proteins, transporter associated with antigen processing (TAP) 1 and 2, are specifically required for this function. Once in the ER, the peptides associate with MHC I, which is comprised of an alpha chain noncovalently associated with beta-2-microglobulin (B2M). A specific molecule called TAP-binding protein (TAPBP), also called tapasin, is involved in peptide loading during MHC I/antigen intracellular transport and expression (figure 1).

The appropriate TCR is capable of binding the peptide and MHC complex (figure 2 and figure 3). CD4 and CD8 act as accessory molecules. They determine whether a particular TCR binds to MHC I or MHC II [3,4]:

●CD8 binds to a nonpolymorphic region of MHC I

●CD4 binds to a nonpolymorphic region of MHC II

TCR chains are also noncovalently linked to nonpolymorphic CD3. Four CD3 chains have been described in humans: epsilon, gamma, delta, and zeta. Signaling cascades are activated upon engagement of the TCR/CD3 complex. CD3 is important in transducing the signal that initiates a T cell activation and differentiation pathway via a motif in the cytoplasmic domain called the immunoreceptor tyrosine-based activation motif (ITAM) (figure 4). (See "The adaptive cellular immune response: T cells and cytokines", section on 'T cell activation and functions'.)

There are a number of molecules involved in early signal transduction, including lymphocyte-specific protein-tyrosine kinase (Lck), Fyn (a tyrosine kinase protooncogene related to Src), zeta-chain-associated protein kinase 70 kilodalton (ZAP-70), and spleen tyrosine kinase (Syk) [1,2]. ZAP-70 deficiency is discussed separately, as is the signaling cascade. (See "ZAP-70 deficiency" and "T cell receptor signaling".)

Proper functioning of CD3, TCR, and the early signaling molecules triggers a distal cascade in the cell culminating in the activation of the Ras-mitogen-activated protein kinase (MAPK) pathway, induction of nuclear factor of activated T cell (NF-AT), and activation of NF-kappa B, with subsequent proliferation, differentiation, and cytokine secretion. Deficiencies in this distal cascade are discussed separately. (See "Severe combined immunodeficiency (SCID): Specific defects".)

TYPES OF DEFICIENCIES — There are multiple molecules associated with the function of the TCR. Defects in these molecules may result in major T cell deficiency or dysfunction. These include the following:

●Defects in TCR itself – TCR defects were initially presumed lethal because no defects had been identified. However, a variant in the TCR alpha subunit constant (TRAC) gene that causes a nonlethal combined immunodeficiency was identified.

●TCR chain V(D)J rearrangement – V(D)J rearrangement of the variable, diversity, and joining segments of the TCR, called V(D)J recombination, requires RAG1 and RAG2. Thus, a deficiency in either enzyme may result in the absence of T cells (as well as B cells since B cells also use these enzymes). Other disorders due to defects in V(D)J rearrangement include deficiencies in Artemis, deoxyribonucleic acid (DNA) ligase IV, Cernunnos, and DNA-protein kinase catalytic subunit (DNA-PKcs).

●T cell binding to peptide MHC – Deficiency of class I or class II major histocompatibility complex (MHC I or MHC II) may result in abnormal CD8 or CD4 function, respectively. MHC deficiency may also cause a lack of maturation of the corresponding T cell subset because MHC is important for thymic selection.

●Noncovalent coupling of TCR to CD3 – CD3 chain deficiency may result in T cell dysfunction.

●TCR/CD3-triggered signaling cascade – Deficiency in the protein kinases, Lck, ZAP-70, Ras homolog family member H (RHOH), and interleukin 2-inducible T-cell kinase (ITK) may cause major T cell dysfunction [5,6].

CLINICAL IMMUNODEFICIENCY SYNDROMES

TRAC deficiency — Two unrelated children from consanguineous families were identified with an identical variant in the TCR alpha subunit constant (TRAC) gene that leads to greatly reduced surface expression of the TCR alpha-beta complex (MIM #615387) [7].

TCR alpha-beta+ T cells were absent, and TCR gamma-delta+ T cells increased. Antibody responses to vaccines and autoantigens were normal. Both reported patients had hypereosinophilia, and one had elevated immunoglobulin E (IgE).

These children presented at 6 and 15 months of age with recurrent respiratory tract infections, candidiasis, and gastroenteritis (Salmonella, Cryptosporidium, rotavirus) that responded to conventional treatment. One of the patients also experienced predisposition to herpes virus infections (varicella zoster virus [VZV], Epstein-Barr virus [EBV], human herpesvirus 6 [HHV-6]). Additional clinical features included failure to thrive, immune dysregulation (eg, vitiligo, alopecia areata, eczema, and autoimmune hemolytic anemia), lymphadenopathy, and hepatomegaly.

Both children successfully underwent transplantation from a matched sibling donor at six to seven years of age.

Defects of V(D)J recombination — RAG1 and RAG2 are needed for the successful variable, diversity, and joining segment (V[D]J) recombination of members of the immunoglobulin gene superfamily (which includes immunoglobulins and TCR chains). A complete deficiency of either enzyme results in severe combined immunodeficiency (SCID) due to the lack of maturation of either T or B cells (T-B-NK+ SCID). Hypomorphic RAG variants are a cause of Omenn syndrome, "leaky"" forms of SCID, and combined immunodeficiency with granulomas and/or autoimmunity [8]. Several variants have been reported, including nonsense and missense variants and deletions. These disorders are discussed in detail separately. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'RAG complex (initiation of recombination)' and "T-B-NK+ SCID: Management".)

Other disorders due to defects in V(D)J recombination include deficiencies in Artemis, DNA ligase IV, Cernunnos, and DNA-protein kinase catalytic subunit (DNA-PKcs). (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)

MHC (HLA) class I deficiency — Some patients with class I major histocompatibility complex (MHC I) deficiency (bare lymphocyte syndrome type I, MIM #604571) have defects in TAP1, TAP2, or tapasin [9-18]. One patient was described with reduced, but not absent, MHC I expression associated with absence of TAP1 and TAP2 proteins [19]. This patient had an absence of both human leukocyte antigen (HLA)-C and HLA-E alleles, which are ligands for killer cell lectin-like receptors and killer cell immunoglobulin-like receptors on natural killer (NK) cells, and had defective NK cell function. Her clinical course was dominated by infections with Streptococcus pneumonia, as well as indolent enlarging skin ulcers positive for herpes viruses and EBV. She had a cousin with a similar clinical phenotype with bronchiectasis and skin ulcers who died at the age of 10 years with severe chronic lung disease. Two other patients, siblings with a variant in TAP1 that resulted in MHC I deficiency, had a clinical course dominated by recurrent sinopulmonary infections that responded well to antimicrobial therapy [20]. Neither one had a history of hospitalization, although one had chronic hepatitis B infection.

Beta-2-microglobulin (B2M) deficiency (MIM #241600) leading to MHC I deficiency has been described in two siblings [21]. One of them suffered from recurrent respiratory tract infections and severe skin disease, whereas the other one was largely asymptomatic other than the development of bronchiectasis. This exact defect has not been identified in other patients with MHC I deficiency.

Clinical features — Abnormalities in the expression of MHC I complexes have been classified into three groups. Due to the small number of patients in each of these groups, the exact pattern of inheritance of MHC I class is not clear. The three groups are as follows:

●Individuals with decreased MHC I expression (approximately 10 percent of normal) do not have an increased incidence of infections and appear to be asymptomatic. The very few individuals identified with this defect were discovered in the process of evaluating a sibling. In this setting, the probable defect is an abnormality in transcription of MHC I [13,16,22].

●Patients with severe reduction of MHC I expression (1 to 3 percent of normal) are healthy during the first year of life. However, by late childhood, frequent upper and lower respiratory tract bacterial infections begin to occur, leading to bronchiectasis and conductive hearing loss [22,23]. Affected patients also have necrotizing granulomatous skin lesions [24]. Some with this particular phenotype have TAP1 or TAP2 deficiency.

●A less-well-characterized group of patients has a combined immunodeficiency phenotype, with recurrent bacterial, fungal, and parasitic infections in the first year of life. These patients have a severe decrease in surface expression of MHC I alpha chain and B2M. The exact molecular deficiency has not been characterized, but transcription defects have been excluded [11,14,16,17].

Laboratory features — Most patients with MHC I expression abnormalities exhibit decreased or absent MHC I expression on the cell surface and decreased NK cell killing activity. However, they have normal antibody-dependent cell-mediated cytotoxicity [25]. Defects of TAP1, TAP2, tapasin, and B2M are usually associated with low numbers of CD8+ T cells. This is an expected finding since MHC I is needed for positive thymic selection of CD8+ T cells.

Diagnosis — Definitive diagnosis is obtained by flow cytometry examination showing decreased MHC I expression on the surface of peripheral blood mononuclear cells (PBMCs). Further genetic testing to determine if there are variants in B2M, TAP1, TAP2, or tapasin is then undertaken.

Differential diagnosis — The differential diagnosis of MHC I deficiency is large. It includes other immunodeficiency syndromes (such as common variable immunodeficiency or ataxia-telangiectasia), as well as other possible etiologies for granulomatous disease (such as chronic granulomatous disease, granulomatosis with polyangiitis, or midline granuloma). (See "Ataxia-telangiectasia" and "Severe combined immunodeficiency (SCID): An overview" and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Treatment — Treatment is directed at infection control. Early and prolonged use of antibiotics should be undertaken at the first sign of infection. Some patients have benefited from immune globulin therapy. Hematopoietic cell transplantation (HCT) is not routinely used for MHC I deficiency, because MHC I expression is not restricted to hematopoietic cells, and, therefore, HCT may not correct all disease manifestations. However, one patient underwent HCT with resultant restoration of MHC I expression and improved CD8 T cell function. The patient's NK cells increased in number but remained functionally impaired [19]. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Immune globulin therapy in inborn errors of immunity".)

MHC (HLA) class II deficiency — Class II major histocompatibility complex (MHC II) deficiency (bare lymphocyte syndrome type II, MIM #209920), an autosomal recessive disease, has been reported in approximately 100 patients worldwide. Both constitutive and induced MHC II expressions are compromised.

Four distinct genetic groups, called complementation groups, can be identified based upon four MHC II-specific transcription factors. The majority map to chromosome 19p12 (regulatory factor X, ankyrin repeat-containing [RFXANK]). The other three defects map to 16p13 (MHC II, transactivator [MHC2TA] gene or class II transactivator [CIITA] protein), 1q21.1-21.3 (regulatory factor X, 5 [RFX5]), and 13q14 (regulatory factor X-associated protein [RFXAP]).

These genetic groups can be simplified into two populations depending upon the presence of regulatory factor X (RFX). RFX is a DNA-binding protein complex that binds in vitro to the X box of class II promoters. Patients from one group (whose defect maps to chromosome 16p13) have normal RFX expression, while the other three groups do not [26-29].

The exact molecular defects have not been identified in most patients but are suspected to involve variants in these MHC II promoter complex DNA-binding regulatory factors (CIITA, RFX5, RFXAP, and RFXANK). The majority of identified defects are RFXANK variants [30]. A variant in the RFX complex subunit RFXAP was identified in several patients [31-33], and variants in RFX5 and MHC2TA (CIITA) have also been reported [34,35]. A report identified MHC II deficiency on TREC analysis done as part of the newborn screening program for SCID [36]. This infant had decreased TREC, severe CD4 lymphopenia, decreased response to mitogen stimulation, and a skewed TCR repertoire, with a stop codon change in his RFX5 gene. In contrast, a report of five patients with MHC II deficiency found detectable TREC [37]. These patients had novel variants in RFXAP, RFX5, and CIITA genes. Of eight tested patients from Egypt with MHC II deficiency, four had RFXANK variants, three had RFX5 variants, and one had a CIITA gene variant while none carried RFXAP variants [38].

Clinical features — MHC II deficiency generally results in a clinical picture of SCID since MHC II plays a pivotal role in the maturation and function of both T and B cells. However, milder cases have been described [39,40].

Most patients present with viral, bacterial, fungal, and/or protozoal infections. Common disorders include pneumonitis, bronchitis, gastroenteritis, and septicemia. Infections usually start in the first year of life and are associated with failure to thrive, diarrhea, and malabsorption [41,42]. In an Egyptian cohort of 10 patients with MHC II deficiency, these patients had failure to thrive, diarrhea, pneumonia, and septicemia due to coagulase-negative staphylococci and Candida krusei [38]. Three of the nine patients who received the live-attenuated polio vaccine developed acute flaccid paralysis, while the nine patients who received Bacillus-Calmette Guérin (BCG) had no complications. A fatal case of vaccine-associated paralytic poliomyelitis was also reported [43].

Laboratory features — The following laboratory findings are observed (table 1):

●Normal number of B cells in peripheral blood (there is one case report of a patient with a novel variant in RFXANK who had <1 percent B cells in the peripheral blood [44])

●Hypogammaglobulinemia

●Poor specific antibody responses

●Normal number of T cells in peripheral blood

●CD4 lymphopenia, with a proportional increase in CD8

●Normal in vitro T cell response to phytohemagglutinin (PHA)

●Decreased in vitro T cell response to antigens

●Complete absence of MHC II expression on B cells

●Slight decrease in MHC I expression

Diagnosis and differential diagnosis — The diagnosis of MHC II deficiency is based upon the finding of absent MHC II expression on PBMCs by flow cytometry. An attempt should then be made to identify the exact genetic defect. The differential diagnosis includes other immunodeficiency syndromes, with combined antibody and cellular immune abnormalities. Diagnostic criteria are shown in the table (table 2). (See "Severe combined immunodeficiency (SCID): An overview".)

Treatment — Therapy is supportive and is aimed at reducing infections with the administration of antibiotics and immune globulin therapy. HCT can be curative, although the success rate is lower than for other combined immunodeficiency diseases [45]. The chances for success are higher if the transplant is performed in the first two years of life [46]. Patients generally die before five years of age without transplantation. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Immune globulin therapy in inborn errors of immunity" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

CD3 deficiency — CD3 chains play a major role in signaling through the TCR since they possess the immunoreceptor tyrosine-based activation motif (ITAM) in their cytoplasmic domain [47]. CD3 deficiency, which appears to have an autosomal recessive pattern of inheritance, has been reported in several patients.

Clinical features — Patients with CD3 delta, CD3 epsilon, or CD3 zeta deficiencies typically have an SCID phenotype, including the absence of T cells and normal, but nonfunctional, B cells (due to the lack of T cell help). Patients with CD3 gamma deficiency have varying phenotypes, with some having SCID-like symptoms and some having a more benign course, often marked by immune dysregulation [47-60].

Variations in clinical phenotype are based in part on the severity of the genotypic abnormality:

●CD3 gamma deficiency (MIM #615607) – The clinical manifestations can include recurrent infections but may be limited to autoimmune diseases [61,62]. CD3 gamma variants can result in decreased diversity and suppressive function of T regulatory cells, perhaps explaining the increased incidence of autoimmune disease in these patients [63].

One patient with CD3 gamma deficiency had features of combined immunodeficiency, including failure to thrive, intractable diarrhea, and recurrent lung infections starting at age 11 months. This boy also had celiac disease and autoimmune hemolytic anemia. He died at 32 months of age from viral pneumonia [56].

A second patient, the brother of the previous child, had the same molecular defect (compound heterozygote for two different point variants). Unlike his brother, he had infrequent minor infections and was still alive at age 10 years. However, he did develop autoimmune dilated cardiomyopathy [50,51]. This difference in clinical phenotype is at the heart of a debate on the limitations of identifying gene defects in the diagnosis of primary immunodeficiencies. Gene variant analysis needs to be used in combination with biomarkers for diagnosis and may be useful for genetic counseling and determining prognosis [64].

A third patient, unrelated to the above two individuals, presented at six months of age with upper respiratory tract infections and urinary tract infections. At the age of two years, he spontaneously recovered from chickenpox. At last report, he was free of infection on intravenous immune globulin (IVIG) [65].

In another report, two patients with SCID due to CD3 gamma deficiency have been described [47].

Two siblings (from a nonconsanguineous family) who had a homozygous splicing variant (intervening sequence [IVS]2-1G>C) in the CD3 gamma gene presented with multiple autoimmune diseases but no significant infections. Laboratory data showed low TCR alpha-beta expression, immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), CD3, CD4, and CD8 in one patient and just low TCR alpha-beta and anti-hepatitis B surface antibody (HBs) titer in the other [61].

●CD3 epsilon deficiency (MIM #615615) – CD3 epsilon deficiency typically results in T-B+NK+ SCID. In a consanguineous family, three offspring with CD3 epsilon deficiency had SCID in association with the complete absence of T cells. The first child died from pneumonitis at five months of age. The second child died at three months of age due to disseminated cytomegalovirus (CMV). The third child died from disseminated adenovirus infection after receiving a haploidentical bone marrow transplantation from the father [58].

By comparison, one child presented with recurrent Haemophilus influenzae pneumonia and otitis media at two years of age. He had no evidence of autoimmune disease. At last report, he was receiving treatment with IVIG and prophylactic antibiotics and was doing well with no major infections [66].

The difference between the individuals with severe disease and the relatively well child lies in the degree of CD3 epsilon deficiency. The mutation in those with severe immunodeficiency, a premature stop codon, resulted in the absence of CD3 epsilon. By comparison, the mutation in the relatively well child did not totally prevent CD3 epsilon expression.

●CD3 delta deficiency (MIM #615617) – CD3 delta deficiency causes T-B+NK+ SCID. Patients presented at two to three months of age with severe, life-threatening viral infection and immunodeficiency [60,66,67].

In one report of three cousins, two died at two to three months of age from multiorgan failure. The third, who was identified at birth, underwent successful bone marrow transplantation and was alive and well at three years of age [66,68].

In a second report of two siblings, the first child presented with CMV pneumonitis and oral candidiasis (thrush). She died from generalized CMV infection at three months of age after HCT for SCID. Her brother, diagnosed at birth, was well after cord blood stem cell transplantation [60,67].

Two unrelated patients were identified with a leaky variant in CD3 delta affecting T alpha-beta but not T gamma-delta cells [69]. These patients presented at 5 and 13 months of age with failure to thrive, diarrhea, and respiratory disease. The younger patient died of multiorgan failure after transplantation, but the older patient was successfully transplanted and was alive and well at four years of age.

Two unrelated patients with atypical (partial) CD3 delta deficiency with a SCID clinical picture were reported [70]. They both had a splicing variant in CD3D (c.274+5G>A) that allowed 50 percent expression of CD3 delta. These patients had a decrease in the number of T cells that expressed TCR alpha-beta but had an enrichment of CD4+ cells that expressed TCR gamma-delta.

●CD3 zeta deficiency (MIM # 610163) – Complete deficiency of CD3 zeta was reported in two patients who presented with T-B+NK+ SCID [71,72]. One of these patients was successfully transplanted. Partial correction of the immunologic phenotype was observed in another patient with CD3 zeta deficiency as the result of somatic reversion [71].

Partial deficiency of CD3 zeta chain expression was reported in a single family. An older sibling was hospitalized at 15 and 17 months of age for bronchitis and was diagnosed with asthma. The younger sibling presented at 11 months of age with recurrent bacterial and viral infections, chronic diarrhea, and failure to thrive. Small bowel biopsy results were characteristic of celiac disease, but the patient did not respond to a gluten-free diet. He died at three years of age after developing severe autoimmune hemolytic anemia [48,71,73].

Laboratory features — The major laboratory finding is the apparent absence of T cells by flow cytometry as T cells are usually enumerated by anti-CD3 epsilon antibodies. Patients with CD3 gamma chain variants also appear to have decreased expression of CD3 epsilon chain. Most patients with CD3 chain deficiency have at least some CD4+ or CD8+ cells in the periphery, the exception being some patients with CD3 delta deficiency, who tend to have a minimal number of T cells. CD3 zeta deficiency results in detectable, but decreased, numbers of T cells. The presence of CD4+ or CD8+ cells without CD3+ cells suggests variants in CD3.

Thus, laboratory findings generally include (table 1):

●Absence of CD3+ cells

●Low numbers or absence of CD2+, CD4+, and CD8+ cells

●Decreased expression of TCR alpha-beta on PBMCs

●Normal numbers of B and NK cells

●Variable antibody response to protein antigens (absent to normal depending upon the defect) and a low response to polysaccharide antigens

●Low in vitro T cell response to mitogens (eg, PHA) and anti-CD3

●Low (among those with CD3 gamma, delta, or zeta deficiencies) or normal (among those with CD3 epsilon deficiency) in vitro response to tetanus antigen and alloantigens

Diagnosis and differential diagnosis — A definitive diagnosis is made via flow cytometry, examining TCR, CD3, CD4, and CD8 expression on the cell surface. If the sum of CD4+ and CD8+ cells is more than the reported number of T cells, CD3 and TCR expression must be examined. It is also imperative to evaluate the intensity of CD3 expression since patients with CD3 gamma deficiency may have an adequate number of CD3 epsilon on the surface of their T cells but in a decreased intensity of expression.

The differential diagnosis includes the other causes for SCID that result in absent T cells in the periphery. (See "Severe combined immunodeficiency (SCID): An overview".)

Treatment — Supportive therapy with antibiotics and immune globulin replacement therapy can be successful. Curative therapy requires HCT [71,74-76]. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Immune globulin therapy in inborn errors of immunity" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Lck deficiency — Several patients have been reported with deficiency of lymphocyte-specific protein-tyrosine kinase (Lck or p56lck), one of the protein tyrosine kinases that is activated upon engagement of the TCR/CD3 complex [77-81]:

●One patient with decreased expression of p56lck and an alternatively spliced transcript lacking the exon 7 kinase-encoding domain was reported. This infant presented with a SCID phenotype, CD4 lymphopenia, and absent CD28 expression on CD8+ T cells [77].

●Another patient, with an aberrantly spliced Lck transcript lacking the entire exon 7, presented with common variable immunodeficiency and CD4 lymphopenia [79].

●Decreased, but not absent or alternatively spliced, Lck was also reported in one patient with idiopathic CD4 lymphopenia [78].

●A homozygous missense variant of the LCK gene leading to weak expression and absent kinase activity was reported in another patient [81].

Uncoordinated 119 (Unc119) is a signaling adaptor protein that associates with CD3 and CD4 and activates Lck [82]. There is a case report of a patient with a variant in UNC119 that resulted in impaired TCR signaling and associated with CD4+ T cell lymphocytopenia [83]. (See "Idiopathic CD4+ lymphocytopenia".)

Clinical features — The first reported patient with p56lck deficiency presented at age two months with failure to thrive, oral candidiasis, sepsis, diarrhea, and hypogammaglobulinemia [77]. Enterobacter cloacae, rotavirus, and CMV were isolated. His course was dominated by persistent CMV infections, failure to thrive, and dependence upon total parenteral nutrition. The patient failed a trial of interleukin 2 and died soon after a bone marrow transplant was performed. Another patient had combined immunodeficiency, with chronic diarrhea, failure to thrive, recurrent sinopulmonary infections, and inflammatory/autoimmune manifestations [81].

The second reported patient with Lck deficiency presented with a picture of common variable immunodeficiency associated with CD4 lymphopenia [79]. Other patients with milder genotypic abnormalities have autoimmune disease (eg, type 1 diabetes mellitus) but no evidence of immunodeficiency [80]. The patient with Unc119 variant presented at age 32 years with recurrent sinusitis/otitis media, frequent episodes of herpes zoster, widespread fungal nail infection, fungal dermatitis, and bronchiolitis obliterans organizing pneumonia [83].

Laboratory diagnosis — The laboratory findings in p56lck deficiency include (table 1):

●CD4 lymphopenia

●Hypogammaglobulinemia

●Normal NK cell number and function

●Progressive decline in the proliferative response to mitogens, interleukin 2, and anti-CD3 stimulation

●An intact response to alloantigens

●Decreased CD28 expression on CD8 cells

●Normal CD28 expression on CD4 cells

●Lack of upregulation of CD69 upon stimulation with anti-CD3

●Normal CD69 upregulation upon stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin

Diagnosis and differential diagnosis — The diagnosis is suggested by flow cytometry analysis of CD4+ cells, showing lymphopenia. However, definitive diagnosis requires the examination of p56lck splicing by reverse transcriptase-polymerase chain reaction (RT-PCR). Differential diagnosis includes other causes of combined immunodeficiency. (See "Severe combined immunodeficiency (SCID): An overview" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Treatment — Treatment is supportive with the administration of antibiotics and intravenous immune globulin (IVIG). Bone marrow transplantation attempted in two patients was unsuccessful.

ZAP-70 deficiency — Zeta-chain-associated protein kinase 70 kilodalton (ZAP-70) deficiency is a rare, autosomal recessive form of combined immunodeficiency characterized by the selective absence of circulating CD8+ T cells and by abundant CD4+ T cells in the peripheral blood. The T cell abnormalities appear to be identical in most of the reported patients. This disorder is discussed in detail separately. (See "ZAP-70 deficiency".)

RHOH deficiency — Two siblings born to first-cousin parents were identified with a homozygous stop codon variant in the ras homolog gene family member h (RHOH) gene that resulted in a functional T cell deficiency [5]. They presented at 20 and 31 years of age with persistent epidermodysplasia verruciformis due to persistent human papillomavirus (EV-HPV) infection and associated comorbidities that included bronchopulmonary disease and Burkitt lymphoma in one patient. The patients' T cells were mostly effector memory T cells with impaired TCR signaling and a marked decrease of the expression of the beta7 integrin subunit.

STK4 deficiency — Serine threonine kinase 4 (STK4), which encodes mammalian sterile 20-like protein 1 (MST1; MIM #604965), is part of a signaling pathway that controls cell growth, apoptosis, and tumorigenesis [84].

This deficiency was first described in 2012 as an autosomal recessive abnormality. Seven patients from three consanguineous families were identified with homozygous mutations in STK4 [85,86]. The age at presentation of these patients ranged from the first one to two years of life to 10 years of age. Two siblings in one of the families died in the first year of life from septicemia (STK4 deficiency suspected but not documented). Common clinical features included recurrent skin and respiratory tract infections (bacterial and viral), bronchiectasis, mucocutaneous candidiasis, extensive molluscum contagiosum, eczematous skin lesions, EBV-associated lymphoproliferative syndrome and lymphoma, and asymptomatic structural cardiac abnormalities. Growth was normal in all patients.

These patients had progressive T cell lymphopenia [85,86]. B and NK cell numbers were low to normal. Hypergammaglobulinemia (IgG, IgA, and IgE) was reported in most patients, while IgM was low to normal. Specific antibody levels were low to normal. Intermittent neutropenia was also reported. A higher rate of lymphocyte apoptosis was seen. One patient was successfully treated with HCT [86]. Her two older siblings died from graft-versus-host disease (GVHD) and infectious complications post-HCT.

Since the initial description, several other patients were reported with this abnormality [85-89]. Consistent features have included viral infections (EV-HPV, EBV, molluscum contagiosum) and bacterial infections. Other reported features include fungal infections (eg, mucocutaneous candidiasis, onychomycosis), mild atopic and seborrheic dermatoses, autoimmune cytopenias, and lymphopenia, depending upon the specific variant [85,88,89]. Patients in two groups had progressive reduction of naïve T cells along with B cell lymphopenia, hypergammaglobulinemia, and autoimmunity [85,86]. Three siblings in another report were found to have deficient leukocyte chemotaxis and adhesion [87]. Examination of innate immunity in an 11-year-old girl with STK4 mutation found significantly impaired type I, II and III interferon responses and reduced but not abolished proinflammatory cytokine response to Toll-like receptor (TLR) 3 and TLR9 [90].

A larger case series reported nine patients with STK4 deficiency [91]. Median age at symptom onset and at diagnosis were similar, ranging from 6 months to approximately 21 years. Main clinical findings were infections (9/9), autoimmune or inflammatory disease (7/9), and allergic disease (4/9). CD4 lymphopenia was present in all nine patients. Characteristics of 15 patients in the literature were also reviewed. Pooling data from all 24 patients, they reported viral infections in 20, recurrent pneumonia in 18, atopic dermatitis in 10, EBV-associated lymphoproliferation in 11, autoimmune cytopenia in 7, and lymphoma in 6. Lymphopenia, CD4 lymphopenia, and elevated IgG, IgA, and IgE were reported, but IgM was low in some of these patients. Supportive therapy with antimicrobials and immune globulin replacement was the mainstay of therapy. HCT was not uniformly successful; some patients did well, while others succumbed. The clinical presentation of STK4 deficiency is similar to hyper-IgE syndrome and should be considered in the differential diagnosis.

ITK deficiency — Interleukin 2-inducible T cell kinase (ITK) is an intracellular tyrosine kinase expressed in T cells. It plays a role in T cell development, proliferation, differentiation, and signaling, similar to Bruton tyrosine kinase (BTK) in B cells. ITK deficiency (MIM #613011) due to homozygous ITK variants causes an EBV-associated lymphoproliferative disorder similar to X-linked lymphoproliferative (XLP) disease or autoimmune lymphoproliferative syndrome. In addition, these patients have increased incidence of lymphadenopathy, splenomegaly, hypogammaglobulinemia, progressive CD4 cytopenia, autoimmune disorders, recurrent infections, and hemophagocytic lymphohistiocytosis. (See "X-linked lymphoproliferative disease" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

The first two patients reported with ITK deficiency had fatal immune dysregulation and B cell proliferation following EBV infection [92]. The older sister presented with severe Candida stomatitis, Pneumocystis jirovecii pneumonia, pleural and pericardial effusion, and hepatosplenomegaly. The younger sister presented with hepatosplenomegaly, abdominal lymphadenopathy, ascites and pleural effusions due to impaired liver function, and EBV-associated Hodgkin lymphoma. A third patient presented with an eight-month history of cough and fever [93]. She was found to have diffuse pulmonary nodules and mediastinal lymphadenopathy with nonmalignant polyclonal B cell proliferation and elevated EBV titers. Several additional patients have been described [6,94-97].

Additional viral infections included CMV and varicella [95]. Some patients also have autoimmune manifestations, including cytopenia, nephritis, thyroiditis, and hemophagocytic lymphohistiocytosis. Laboratory findings include absent NKT cells, CD4+ T cell lymphopenia, and progressive hypogammaglobulinemia [6,92].

The first reported patient went on to develop Hodgkin lymphoma, which was successfully treated, but ultimately died from respiratory failure due to pulmonary infection [92]. Her younger sister died from ischemic brain injury after HCT. The third reported patient was successfully treated with rituximab, the anti-CD20 monoclonal antibody that destroys B cells [93]. Another patient underwent successful HCT after a reduced-intensity conditioning regimen that included rituximab [98].

Hodgkin lymphoma and Hodgkin-like lymphoma are the most common reported malignancies [95,97], although one case of non-Hodgkin lymphoma has also been reported [99].

Other ITK variants leading to ITK deficiency can cause idiopathic CD4+ lymphocytopenia [6] and decreased generation of CD8+ cytotoxic T cells due to an intrinsic defect in degranulation [100]. (See "Idiopathic CD4+ lymphocytopenia".)

LAT deficiency — Linker for activation of T cells (LAT) is a transmembrane adaptor molecule that plays a role in signaling as part of the TCR complex. Homozygous premature stop codon variants lead to a SCID phenotype with absent T cells and normal B and NK cell (T-B+NK+) numbers [101,102]. Patients present with typical SCID features, including severe recurrent infections and failure to thrive in the first few months of life, as well as serious autoimmune disease such as autoimmune hemolytic anemia and immune-mediated thrombocytopenia. Of the eight patients in two case series, three were alive and well after HCT, and the other five had died from infections, autoimmune disease, or complications related to transplantation.

CARMIL2 deficiency — Capping protein regulator and myosin 1 linker 2 (CARMIL2) is associated with the cell membrane and cytoskeleton and is involved in regulation of actin polymerization and cell migration. Loss-of-function variants in CARMIL2 have been reported in four patients [103], two siblings in each of two families with consanguineous parents. All four patients presented with disseminated EBV-positive smooth muscle tumors with homozygous loss-of-function variants in the CARMIL2 gene. These patients lacked regulatory T cells (Tregs) but did not show signs of organ-specific autoimmunity. They also had defective CD28 co-signaling, resulting in abnormal T cell differentiation, and had perturbed cytoskeletal organization.

Seven patients from three unrelated, consanguineous families presented with esophagitis, recurrent skin infections, pulmonary infections, and dermatitis with evidence of combined immunodeficiency [104]. Two novel variants were found in these families. All patients had decreased Treg and a poor response of CD4 cells to CD3/CD28 stimulation, resulting in a dominance of naïve CD4 cells in the peripheral blood. Three Norwegian families with a potential founder variant in CARMIL2 presented with warts, molluscum contagiosum, and T cell dysfunction [105].

Five patients from three unrelated kindreds who had CARMIL2 deficiency presented as very-early-onset inflammatory bowel disease [106]. (See "Genetic factors in inflammatory bowel disease", section on 'Very early onset IBD'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●T cell receptor complex and T cell activation – The T cell receptor (TCR) complex includes a number of components and associated molecules (figure 2 and figure 3). The TCR is a heterodimer, either an alpha and a beta chain or a gamma and a delta chain, that binds to peptide presented on class I or II major histocompatibility complex (MHC I or MHC II) molecules by antigen-presenting cells (APCs). CD4 and CD8 act as accessory molecules. TCR chains are also linked to CD3, which is important in transducing the signal that initiates a T cell activation and differentiation pathway. A number of downstream signaling molecules are involved in this pathway (figure 4). (See 'Overview of T cell receptor biology' above.)

●Types of defects – Defects in the TCR complex or associated molecules cause major T cell deficiency or dysfunction that usually results in a combined immunodeficiency that can be severe. Some specific defects result in an Epstein-Barr virus (EBV) associated lymphoproliferative disorder. (See 'Types of deficiencies' above.)

●MHC (HLA) class I deficiency – Some patients with MHC I deficiency (bare lymphocyte syndrome type I) have been found to have defects in transporter, ATP-binding cassette, major histocompatibility complex, 1 or 2 (TAP1 or TAP2) (figure 1). The inheritance pattern is unclear due to its rarity. The clinical presentation is highly variable, depending upon the amount of MHC I expression. Treatment is directed at infection control (antibiotics and immune globulin replacement therapy). (See 'MHC (HLA) class I deficiency' above.)

●MHC (HLA) class II deficiency – MHC II deficiency (bare lymphocyte syndrome type II) is an autosomal recessive disease. The exact molecular defects are unknown. The clinical picture is one of severe combined immunodeficiency (SCID). Treatment is directed at infection control (antibiotics and immune globulin replacement therapy). Hematopoietic cell transplantation (HCT) can be curative, but experience is limited. (See 'MHC (HLA) class II deficiency' above.)

●CD3 deficiency – CD3 deficiency results from defects in one of the four CD3 chains (gamma, epsilon, delta, or zeta). It appears to have an autosomal recessive pattern of inheritance. The clinical features are highly variable, depending upon the affected chain and variant. Treatment is directed at infection control (antibiotics and immune globulin replacement therapy). HCT can be curative, but experience is limited. (See 'CD3 deficiency' above.)

●Lck deficiency – Deficiency of Lck (p56lck), one of the protein tyrosine kinases that is activated upon engagement of the TCR/CD3 complex, has been reported in several patients. Clinical presentation is variable, depending upon the severity of the variant. Treatment is directed at infection control (antibiotics and immune globulin replacement therapy). (See 'Lck deficiency' above.)

●RAG1, RAG2, and ZAP-70 deficiencies – Recombinase-activating genes 1 and 2 (RAG1 and RAG2) deficiency and zeta-chain-associated protein kinase 70 kilodalton (ZAP-70) deficiency are discussed separately. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "ZAP-70 deficiency".)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.