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The adaptive cellular immune response: T cells and cytokines

The adaptive cellular immune response: T cells and cytokines
Jennifer Heimall, MD
Section Editor:
Luigi D Notarangelo, MD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Feb 2023. | This topic last updated: Jan 30, 2023.

INTRODUCTION — T cells regulate the activities cells participating in immune responses. They provide help for antibody production by B cells, and they are also the effectors of antigen-specific cell-mediated immunity (CMI). CMI is important in the elimination of intracellular infections (eg, viruses, mycobacteria, and some bacteria) and aberrantly differentiating cells (eg, neoplasms). CMI also destroys allogeneic cells (graft rejection). In addition, it is involved in cellular autoimmune responses, as well as type IV allergic reactions to drugs and contact dermatitis. Furthermore, T cells activate innate immune cells such as phagocytic cells to become more effective at killing other types of pathogens such as fungi. (See "Transplantation immunobiology" and "Overview of autoimmunity" and "Drug hypersensitivity: Classification and clinical features", section on 'Type IV reactions' and "Overview of dermatitis (eczematous dermatoses)", section on 'Allergic contact dermatitis'.)

T cell receptors (TCRs), in contrast to immunoglobulins, exist only as multimeric membrane-bound complexes and are not secreted intact in soluble form. Also unlike immunoglobulins, TCRs recognize fragments (peptides) of protein or glycoprotein antigens in complexes with major histocompatibility molecules on the surfaces of antigen-presenting cells (APCs, also called accessory cells) or on targets of cytotoxicity. Note the distinction between the processed antigen (peptide) eliciting a response and the major histocompatibility complex (MHC) antigen with which it becomes associated to stimulate peptide-specific T cells. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation' and "Normal B and T lymphocyte development".)

The cellular interactions that form the basis of CMI are discussed in this topic review. Related topics and T cell help for antibody production are discussed separately. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation' and "Normal B and T lymphocyte development" and "The adaptive humoral immune response".)

ANTIGEN-PRESENTING CELLS — T cell responses are initiated by antigen-presenting cells (APCs), which are reviewed briefly here and discussed in greater detail elsewhere. (See "Antigen-presenting cells".)

Dendritic cells (DCs) are the predominant class of "professional" APCs [1]. The main subtypes include plasmacytoid DCs (pDCs) and conventional DCs (cDCs). These are further divided into additional subtypes that have distinct surface marker expression, morphology, tissue distribution, and cytokine production. These different types of DCs lead to distinct pathways of T cell stimulation. Monocytes/macrophages may also exert some APC activity, and monocytes may differentiate into DCs.

Only APCs constitutively express major histocompatibility complex (MHC) class II molecules (which are required for activation of CD4+ T cells) and display the necessary costimulatory signals. The great majority of somatic cells express MHC class I molecules and can serve as targets of CD8+ cytotoxic T cells.

B cells express MHC class II molecules, which are required to receive T cell help (see "The adaptive humoral immune response"). Although they are not strong enough to activate resting naïve T cells, B cells may stimulate memory T cells. (See 'Memory T cells' below.)

DCs use a system of pattern recognition receptors, such as "Toll-like" receptors (TLRs), that bind to a variety of microbial products, including bacterial lipopolysaccharide, flagellin, and lipopeptides. These receptors stimulate development and migration of immature DCs in the periphery. Under the influence of cytokines and chemokines, DCs mature and migrate into the secondary lymphoid tissues where they interact with T and B cells in T zones of the lymph nodes, Peyer patches, and the spleen. Cysteine-cysteine motif chemokine receptor (CCR) 7 and cysteine-X-cysteine motif receptor (CXCR) 5 both act to assist DC, T, and B cell trafficking to lymphoid tissues [2]. (See "Toll-like receptors: Roles in disease and therapy".)

DCs are highly active in processing and presenting antigen to T cells. Antigen is taken up via several means (macropinocytosis, in immune complexes via immunoglobulin G [IgG] Fc receptors, etc). The antigen is then degraded, and peptides are loaded onto MHC class I or class II molecules. Intracellular-derived antigens (intracellular self-proteins or products of organisms that replicate intracellularly) are predominantly presented via MHC class I molecules and extracellular antigens mainly via MHC class II molecules. However, there is significant overlap in these pathways. (See "Major histocompatibility complex (MHC) structure and function".)

CYTOKINES — Immune cells produce a variety of products that allow them to communicate with each other and orchestrate an explosive, yet self-limited attack. Cytokines are hormone-like glycoproteins that enable immune cells to communicate with one another by either direct contact or through the secretion of soluble mediators. They play an integral role in the initiation, perpetuation, and subsequent downregulation of the immune response (table 1).

Direct cell-cell contact regulates immune function of adjacent cells by a variety of mechanisms, including membrane-bound cytokines such as tumor necrosis factor (TNF) alpha. In contrast, release of soluble mediators into the environment permits cells to exert influence at a distant site within the tissue. In some cases, cytokines can even reach distant cells in other organs via the peripheral circulation. For instance, interleukin (IL) 6 produced at a local inflammatory site can enhance liver acute-phase protein production. Soluble cytokines bind to a specific receptor on the surface of target cells and transduce a signal that alters cellular function.

The migration of immune cells is accomplished by a highly redundant family of cytokines known as chemokines. These factors, which are classified by their amino acid sequence and their inflammatory and immune regulatory homeostatic roles, bind to specific surface receptors that induce cells to migrate into tissues [3]. However, there is plasticity to the relationship of chemokines binding to their receptors such that loss of a single chemokine receptor does not lead to a profound loss in the ability of immune cells to migrate and carry out their intended functions [4]. The roles of chemokines include induction of cellular migration, local cellular activation and survival, and homeostatic regulation of immune cells.


T cell receptor-CD3 complex — The T cell receptor (TCR) alpha-beta (TCR2) or gamma-delta (TCR1) heterodimer is noncovalently associated with the CD3 complex on the cell membrane. There are four types of CD3 subunits: gamma, delta, epsilon, and zeta. CD3 complex is comprised of gamma-epsilon and delta-epsilon heterodimers and a zeta homodimer in most cells. The gamma and delta chains of CD3 are distinct from the gamma and delta forms of the TCR itself. The CD3 complex is expressed on all T cells. The complex has a critical role in transducing a signal of TCR contact across the lymphocyte membrane (figure 1). The interaction of the TCR with a complementary complex of peptide plus major histocompatibility complex (peptide-MHC) forms the basis of the antigen specificity of T cell activation by antigen-presenting cells (APCs) and target cell recognition in cell-mediated immunity (CMI). (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

T cell accessory molecules — T cells are categorized based upon cell surface expression of one of two coreceptor molecules, either cluster of differentiation (CD) 4 or CD8. CD4 and CD8 have great importance for T cell development and for antigen recognition and activation of mature T cells (see "Normal B and T lymphocyte development"). CD4+ cells recognize antigen presented by a MHC class II, while CD8+ cells recognize antigen presented by an MHC class I.

There are a host of additional cell surface molecules that play roles in T cell interactions with other cells including T cell activation by APCs, T cell regulation of other T cells and B cells, and cytotoxic T cell killing. Some of these are adhesion molecules, others are mainly transducers of activating or inhibitory signals, and several have multiple functions. Some of these T cell accessory molecules are summarized in the table (table 2).

T cell circulation — Upon their egress from the thymus, naïve T cells circulate throughout the body in both the blood and lymph fluids. Naïve T cells circulating through secondary lymphoid tissues, such as spleen, lymph nodes, and Peyer's patches in the intestine, encounter dendritic cells (DCs) that have similarly migrated to these tissues to present antigens. The naïve T cells "scan" the antigens presented by the DCs. When an antigen-MHC complex of suitable affinity is identified, the naïve T cells are activated [5]. Since naïve T cells continually recirculate through the blood, spleen, lymph, lymph nodes, and other tissues [6] throughout the body, they are able to sample antigens derived from a wide range of distinct anatomic sites.

Following engagement of the appropriate complementary complex, the activated naïve T cells proliferate. Activated T cells also migrate toward the periphery of the T cell-rich areas in the secondary lymphoid organs to facilitate contact with the B cell-rich areas. This permits interactions with antigen-specific B cells, thereby providing T cell help for antibody production. (See "The adaptive humoral immune response".)

Activated naïve T cells may either become effector T cells, which are then able to further differentiate to memory cells, or they may directly differentiate to become memory T cells. Most effector T cells will then migrate from the lymphoid organs into the peripheral circulation and tissues. This permits effector T cells to reach sites of infection.

T cell activation via the two-signal model — The paradigm for T cell activation is the so-called "two-signal" model (figure 1). All of the cell surface molecules listed in the table may play a role in T cell activation (table 2). During intercellular contact, many of these molecules interact with cytoskeletal elements and are organized into specific regions within the zone of contact named the "immunologic synapse" (figure 1) [7].

The two-signal model of T cell activation includes the following:

Signal 1 derives from contact of TCR-CD3 with a peptide-MHC complex.

It is possible, particularly where agonist (foreign) peptide-MHC complexes occur at very low density on the APC surface, that endogenous (self) peptide-MHC complexes also participate in the initiation of the immunologic synapse [8].

Signal 2 derives from costimulatory pathways.

A tremendously complex cascade of events within the cytoplasm ensues upon receptor and costimulator ligation (figure 2) [9]. TCR signaling is discussed in detail separately. (See "T cell receptor signaling".)

Binding of TCR-CD3 without engaging any costimulating molecules leads to a state of anergy (unresponsiveness or refractoriness to activation) and possibly even to deletion by apoptosis (death) [10]. This may be an important mechanism in T cell tolerance. (See "Apoptosis and autoimmune disease".)

The mechanism by which costimulation leads to activation rather than anergy is unknown. The interaction between CD28 expressed on T cells and CD80 and CD86 (B7-1 and B7-2) expressed on APCs is a very potent costimulatory system [10]. T cells express CD154 (CD40 ligand, CD40L) following activation via the TCR. CD40L binds to CD40 expressed on the APC surface and induces expression of CD80 and CD86 by the APC. Binding of these to CD28 on a resting T cell will not activate the cell, but, once a T cell has been "primed" by antigen exposure, ligation of CD28 can trigger production of interleukin (IL) 2 and cellular proliferation. The simultaneous production of the cytokine IL-2 and a component of its high-affinity receptor (IL-2R-alpha or CD25) initiates a positive feedback loop that is important for T cell proliferation.

Inducible T cell costimulator (ICOS) is a CD28 homolog that is inducibly expressed on activated T cells [10]. Interaction with ICOS ligand (ICOS-L, a B7 homolog) may augment T cell activation. However, ICOS also appears to have other roles in modulating IL-10 production by regulatory T cells (Tregs) and inhibiting development of T helper type 17 (Th17) cells. (See 'Treg' below and 'Th17' below.)

A wide variety of additional signaling molecules expressed on T cells and APCs influence the activation or suppression and differentiation of T cells into effector/memory or regulatory cells [10].

CD4+ T cell activation — The following sequence of events takes place during activation of CD4+ T cells:

DCs capture and process antigen from peripheral sites. They then migrate into lymph nodes and develop into mature APCs.

Naïve T cells "scan" DCs with their TCR, looking for complementary peptide-MHC.

Antigen recognition triggers a complex cascade of intercellular membrane glycoprotein contacts and intracellular biochemical signals.

The T cell-APC (or other cell) interaction is modulated by alterations in the expression of surface molecules and cytokine secretion by both cells.

Specific characteristics of the cytokine milieu and the combination of signals results in either activation or tolerization of the T cell. It also determines the effector phenotype of an activated cell.

The activated/effector T cell may then migrate into peripheral tissues or undergo further interactions with other cells (eg, B cells) within lymphoid tissues.

Cytokine profiles and functions of CD4+ T helper cell subsets — Activated CD4+ T cells are subdivided into distinct functional categories depending upon the profile of secreted cytokines (figure 3 and table 3 and table 1) [11]. The conditions under which a T cell is stimulated have great influence on the functional phenotype of the activated cell. The route by which antigens enter the body (eg, skin, gut, etc), the form of the antigen (inert molecules, living microorganisms), and the amount of antigen are all important factors that impact the differentiation to these functional T cell subsets.

At the cellular level during T cell stimulation, the degree of TCR occupancy, the activity of various costimulatory pathways, and the presence of certain cytokines all influence the phenotype of activated cells. As examples, IL-12 and interferon (IFN) gamma are the cytokines that drive T helper type 1 (Th1) cell development, while IL-4 is critical for determining T helper type 2 (Th2) development (table 1).

These helper T cell subpopulations are not easily distinguished with respect to surface markers. Thus, they are usually identified by their cytokine production. In general, each of these cytokine production subtypes does not amount to more than 2 to 5 percent of the T cells in circulation, usually less. These proportions are highly variable and depend upon many factors such as chronic and/or acute infection and inflammation, the genetic makeup of the individual, and modifying environmental factors. Proportions of one or more subsets may be higher in lymphoid or other tissues, again depending upon the specific tissue and ongoing immunologic processes. (See "Normal B and T lymphocyte development".)

Several subsets have been distinguished for CD4+ T cells. These can be grouped into those associated with effector activities (Th1, Th2, Th9, Th17, Th22, and follicular helper T cells [Tfh]) and those with regulatory activities (natural regulatory T cell [nTreg], induced regulatory T cell [iTreg (type 1 regulatory T cell [Tr1])], Th3) (figure 3) [11]. The Th1 and Th2 patterns have been most extensively studied. These patterns are to some degree mutually exclusive, as one pattern often clearly predominates in the context of a particular immune response.

Th1 — T helper type 1 (Th1) responses promote production of opsonizing antibodies (eg, IgG1) and induction of cellular cytotoxicity and macrophage activation. Th1 cells secrete IFN-gamma and IL-2 but not IL-4. They activate macrophages and help in the eradication of intracellular micro-organisms, such as mycobacteria and viruses. Th1 cells also promote cytotoxic T cell development and delayed-type hypersensitivity (DTH) reactions. Hence, Th1 cells are proinflammatory and may be involved in the pathogenesis and maintenance of some autoimmune diseases.

Th1 cells express both chains of the IL-12 receptor (IL-12-R-beta-1 and IL-12-R-beta-2) [12,13], as well as cysteine-X-cysteine motif receptor (CXCR) 3 and cysteine-cysteine motif chemokine receptor 5 (CCR5) [12,14-16]. Th1 responses are promoted by local release of the IL-12 superfamily of cytokines including IL-27, IL-23, and IL-12. IL-12 may favor IFN-gamma release, whereas IL-23 may favor IL-17 release. These responses are further enhanced by IL-15 and IL-18 production by DCs and macrophages.

T-bet promotes Th1 development by direct induction of IFN-gamma and IL-12-R-beta-2 chain gene transcription [17,18]. In addition, T-bet appears to inhibit IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA-binding protein 3 (GATA3) from interacting with its target DNA [19].

Th2 — T helper type 2 (Th2) cells produce IL-4, IL-5, IL-13, and IL-10 but not IL-2 or IFN-gamma. By virtue of their IL-4 and IL-13 secretion, they are important in the promotion of immunoglobulin E (IgE) synthesis and via IL-5 stimulate eosinophil development. They help mediate immunity against parasitic infestations, particularly helminths, and are pivotal in the development of allergy and asthma [20-22].

Th2 cells express IL-12-R-beta-1 [12,13] and IL-4 receptors [23]. CCR3, CCR8, and CCR10 are also expressed by Th2 cells [12,14-16]. Th2 responses are favored by synergistic local production of IL-4, IL-33, and IL-18. GATA3 is pivotal for Th2 maturation [17,18].

Th9 — T helper type 9 (Th9) cells produce IL-9 and IL-10. Th9 development from naïve Th cells is mediated by transcription factors signal transducer and activator of transcription (STAT) 6 and PU.1 (binds to a purine-rich DNA sequence called the PU-box) [24,25] in the presence of transforming growth factor (TGF) beta, IL-2, and IL-4. These cells have a role in antitumor immunity, allergy, and autoimmune disease [26]. They are also thought to be important in resistance to parasites and may be involved in asthma and other allergic disease [27,28]. PU.1 has a negative effect on the expression of CD40L in CD4 cells and downregulates IL-21 expression as well, leading to decreased germinal cell B cell expansion and reduced IgG production [29].

Th17 — T helper type 17 (Th17) cells secrete IL-17A, which induces production of proinflammatory cytokines (IL-17F, IL-22, IL-26) and chemokines (CCL20) and recruits neutrophils [12]. Th17 cells appear to be involved in the early response to numerous extracellular pathogens, including bacteria and fungi, and play an important role in driving chronic inflammatory responses in chronic infection, allergy, and autoimmunity [30,31]. They may also play a role in the neutrophil, rather than eosinophil, predominant forms of asthma [32].

Th17 cells express only IL-12-R-beta-1 [12,13]. Th17 cells express the IL-23 receptor, a heterodimer comprised of IL-12-R-beta-1 and a unique IL-23-R chain, in addition to receptors for IL-6, IL-21, and TGF-beta [12,33]. CCR2 and CCR6 are expressed by Th17 cells [12,14-16]. Retinoid-related orphan receptor gamma t (RORgT) is critical for Th17 maturation [17,18].

Th22 — T helper type 22 (Th22) cell production is upregulated by RORgT and downregulated by Tbet. Th22 cells are a major source of IL-22, although this cytokine is also produced by Th17 cells [34]. When IL-22 is cosecreted with IL-17, the effect tends toward more proinflammatory outcomes, particularly in psoriasis. In asthma and atopic dermatitis, increased frequency of IL-22 cells is associated with increased disease severity. Th22 cells can also have a protective role in mucosal immunity [35].

Tfh — T follicular helper (Tfh) cells are preponderant in germinal centers in secondary lymphoid tissues where they have a prominent role in providing help to B cells for high-affinity antibody production [36-38]. IL-12 may be crucial to Tfh development [39]. Circulating Tfh express high levels of the chemokine receptor CXCR5 [40].

Naïve CD4 T cells differentiate to Tfh cells when the transcription factor B cell lymphoma 6 protein (BCL6) is expressed along with high levels of CXCR5, which allows these T cells to migrate to and reside in the germinal centers of lymph nodes [41]. Tfh resident in lymph node germinal centers can be characterized by the surface markers CCR7loPSGL1loCXCR5hi,PD-1hi, ICOShi [40]. The development of Tfh cells is inhibited by B lymphocyte-induced maturation protein 1 (Blimp-1) and STAT5. IL-12, IL-23 and TGF-beta are the initiating cytokines for Tfh differentiation [39]. IL-1 and IL-6 signaling through STAT3 are also important in the differentiation of Tfh. In the presence of appropriate cytokines and B cell interactions, Tfh cells can differentiate into Th1-like, Th2-like, or Th17-like Tfh cells [36].

Treg — T regulatory (Treg) cells are central to the establishment and maintenance of peripheral tolerance. They play a principal role in negative regulation (suppression) of the immune response. Treg cells typically comprise 1 to 2 percent of the total CD4 population, but overall are critically responsible for the suppression of effector CD4 T cell effects through contact inhibition of activity between APC and effector T cells or direct cytotoxicity.

Development of nTregs is mediated by the transcription factor forkhead box P3 (Foxp3), which leads to surface expression of cytotoxic T lymphocyte antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), killer cell lectin-like receptor G1 (KLRG1), CD25, and Blimp-1. Treg cells also commonly express CD134 (OX40), CD27, and CD62-L and secrete TGF-beta, IL-10, and also IL-35, a novel member of the IL-12 superfamily [42]. Their effector function is often dependent upon cell contact-mediated cellular suppression. (See 'Suppression' below.)

iTreg — Induced T regulatory (iTreg) cells can be induced in the periphery after antigen priming in the presence of retinoic acid and TGF-beta.

Th3 — T helper type 3 (Th3) cells are important in mucosal tolerance induction and may promote development and/or maintenance of induced Treg cells [43].

CD8+ T cell activation — Cytotoxic T cells (cytotoxic T lymphocytes [CTLs]), the majority of which express the CD8 coreceptor for MHC class I, are also activated by professional APCs in lymphoid tissues, as are CD4-bearing cells. However, the APC must first be activated by contact with an antigen-specific CD4+ T cell before it is capable of inducing a naïve CD8+ cell to become a full-fledged effector (cytotoxic) T cell [44]. Direct CD4+ T cell help may also be required for primary CD8+ T cell responses in the face of viral challenge, in particular by increasing IFN-gamma and Fas ligand (FasL) expression [44,45].

As mentioned above, virtually all nucleated cells process cytoplasmic molecules and present them on their surfaces in association with MHC class I molecules (see 'Antigen-presenting cells' above). Thus, antigens derived from pathogens that replicate intracellularly are presented in this manner. Professional APCs may also present antigens internalized by phagocytosis via MHC class I molecules [1]. The degree to which MHC molecules bearing antigen cluster on the cell surface appears to affect the sensitivity of T cell recognition [46].

Cytotoxic T lymphocyte function — After acquiring effector function in lymphoid tissues, cytotoxic cells circulate in the periphery, "searching" for infected cells to kill. The first step in lysis is membrane contact between the cytotoxic and target cells presenting antigens specific to the TCR, forming the immunologic synapse. This contact is mediated by the TCR/CD8-MHC class I interaction, as well as by several T cell/target cell adhesion molecule interactions (eg, CD2 with CD58, CD11a/CD18 with CD54CD54 and others) [47].

Cytotoxicity occurs via two principal mechanisms: granule exocytosis and expression of FasL. In addition to these cytotoxic mechanisms, CTLs also secrete a variety of cytokines, such as IFN-gamma and TNF, that may directly damage target cells or inhibit microbial replication [47]. They also recruit and modulate additional inflammatory effector cells, such as macrophages.

Natural killer (NK) cells express a cytotoxicity activating molecule called natural killer group 2 D (NKG2D or killer cell lectin-like receptor, subfamily K, member 1 [KLRK1]). Two ligands for NKG2D are MHC class I-like molecules MHC class I chain-related gene A (MICA) and ULBP4 (binding protein 4 for the cytomegalovirus-encoded glycoprotein UL16). CTLs also express NKG2D, and cytotoxicity of these cells can also be promoted by interaction with MICA and ULBP4 [48]. The latent membrane protein 2A (LMP2A) on the surface of Epstein-Barr virus (EBV) transformed cells can reduce expression of or interfere with the interaction of MICA and ULBP4 with NKG2D and inhibit CTL recognition of EBV transformed B cells.

A single CTL may "recycle" and lyse several target cells without itself suffering damage. It is unclear how CTLs are protected from the destructive potential of the molecules they discharge. CTLs are not themselves immune to lysis, since they may themselves be the targets of other cytotoxic cells.

Granule exocytosis — Following contact with the target cell, lytic granules within the CTL gather near the immunologic synapse (a process called "polarization"). The membranes of the granules fuse with the CTL membrane and release their contents directly adjacent to the target cell. CTL granules contain a variety of substances that enter the target cell and initiate apoptosis (programmed cell death). Granule contents enter the target cell through pores in the membrane created by the protein perforin, which has homology with complement factor C9. The molecules that initiate the cytotoxic process within the target cell are a family of at least 11 serine proteases called granzymes [47]. Although much of the biochemistry of granzymes is still unclear, some of their substrates may be precursor forms of caspases, a group of cytoplasmic enzymes that can trigger apoptosis [47].

CD27 is an activation marker for both T cells and B cells. It is a member of the TNF receptor superfamily (TNFRSF7). Its ligand is CD70 (TNFSF7). All of the biologic activities of the CD27–CD70 interaction are not yet well understood. It has been established, however, that EBV-infected B cells express very high levels of CD70. The interaction of CD27 on CTLs with CD70 on EBV-infected B cells greatly enhances granule-mediated cytotoxicity by CTLs [49].

Fas ligand — The other principal means of cell killing involves expression of FasL (or CD95L) on the surface of the effector CTL. If the target cell expresses the Fas molecule (CD95), ligation by FasL on the CTL will initiate a program of apoptosis in the target cell [47]. It is unknown precisely under what circumstances a CTL will use one mechanism or the other. Of course, FasL expression is not relevant for target cells that do not express Fas. Note that the CD27–CD70 interaction does not appear to enhance Fas–FasL mediated killing [49].

Memory T cells — When naïve T cells are activated, some become short-lived effector T cells, while others become long-lived memory T cells. In comparison with naïve T cells, memory T cells are activated more easily and rapidly in secondary immune responses [50]. This results from alterations in surface molecules, as well as intracellular differences in signaling (table 4) [50]. There may be many distinct functional classes of memory T cells having different migration patterns within tissues, different properties with respect to ease of stimulation and kinetics, and requirements for maintenance. However, these issues require much additional study.

Some convenient markers of memory T cells are CD45 and the CC (two adjacent cysteines) chemokine receptor CCR7. The CD45RA isoform is expressed on naïve T cells. The CD45RO isoform is expressed on activated or memory T cells. While CD45RA alone effectively distinguishes naïve CD4 cells in most circumstances, it is not as useful for CD8 cells, because a significant proportion of memory CD8 cells may revert to CD45RA expression. These markers may be used as follows [51,52]:

CD45RA+ (or CD45RO-)/CCR7+ = Naïve T cells.

CD45RA- (or CD45RO+)/CCR7+ = Central memory T cells.

CD45RA- (or CD45RO+)/CCR7- = Effector memory T cells.

CD45RA+ (or CD45RO-)/CCR7- = T effector memory RA-expressing cells (TEMRA). These cells occur much more commonly in the CD8 compartment, and this is sometimes called an "exhausted" type of cell, which is no longer capable of robust cytokine production or cytotoxicity. These cells are seen sometimes in the setting of chronic infections or autoimmune disease [53].

The proportion of naïve cells is high (>70 to 90 percent of peripheral T cells) at birth and gradually declines with age. By late childhood or adulthood, naïve cells are <50 percent of peripheral T cells (table 5 and table 6) [54].

CELLULAR REGULATION OF IMMUNE RESPONSES — Immune effector mechanisms are powerful processes of cell and tissue destruction. It is of clear benefit to maintain close control over immune system activation so that there is not unnecessary exposure to its degradative potential. T cells are critical in the regulation of both humoral (antibody) and cellular effector mechanisms. Antibody responses to the vast majority of protein and glycoprotein antigens require T cell help. Regulatory T cells (Tregs) also control specific cellular cytotoxicity [55,56]. T cell regulation is mediated by cellular contacts and soluble factors.

Positive regulation

Cognate T helper cell-B cell interaction — As discussed separately, effective antibody production against T dependent antigens (most proteins and glycoproteins) requires cellular contact between B cells and T helper cells, as well as cytokine production by T cells. Naïve T cells may be activated by antigen-presenting cells (APCs). They subsequently become effectors capable of activating antigen-specific B cells that display the appropriate combination of peptide plus major histocompatibility complex (peptide-MHC). (See "The adaptive humoral immune response".)

Activation of antigen-presenting cells — The T cell-APC interaction also results in an activated "effector" APC. This cell is then capable of elaborating higher concentrations of cytokines, increased phagocytosis, and intracellular killing, as well as the capacity to activate cytotoxic T cells.

Negative regulation

Autoregulation via CTLA-4 — After activation, T cells reduce expression of CD28 and increase expression of cytotoxic T lymphocyte antigen 4 (CTLA-4), which has higher affinity for the ligands CD80 and CD86 (B7-1 and B7-2). This leads to loss of costimulation through CD28, resulting in cessation of proliferation and cytokine production.

Inhibition via PD-1 — Programmed cell death 1 (PD-1) is an inhibitory homolog of CD28 that is expressed late after T cell activation [10]. PD-1 interacts with the inhibitory B7 homologs programmed death ligands (PD-L) 1 and 2. Ligation of PD-1 leads to inhibition of cytokine secretion and other effector functions of T cells.

Activation-induced cell death — Following activation, T cells expand clonally, yielding large numbers of cytokine-producing cells. These activate potent inflammatory responses to combat infection. Unchecked T cell activation could lead to malignant proliferation or autoimmune disease. Thus, one fundamental mechanism of negative regulation of T cells is activation-induced cell death (AICD) [57]. The same signals that lead to activation also set in motion a program of cell death (apoptosis) that may eventually kill the cell.

Two important receptors promoting death of activated T cells are Fas (CD95, which binds Fas ligand [FasL]) and tumor necrosis factor (TNF) receptor 2 (TNFR2 or CD120b, which binds TNF-alpha). The interactions between these ligand pairs may occur on the same cell or between different cells. That is, the mechanism may be one of "suicide" or "homicide." (See "Apoptosis and autoimmune disease".)

Suppression — Most T cells die within the thymus, either because they do not interact effectively with self-MHC molecules or they display reactivity against self-components (see "Normal B and T lymphocyte development"). However, this process is not perfect, and some self-reactive mature T cells exit the thymus and reach the periphery [58]. These cells must be inactivated (ie, made anergic) in order to prevent autoimmune disease. In addition, there must be a process to extinguish a protective immune response when it is no longer necessary. Mechanisms of immune suppression or regulation serve both of these functions.

Role of cytokines in negative feedback — In addition to positive feedback loops involving cytokines, many negative feedback signals downregulate the immune system. This prevents an inflammatory response from overwhelming and harming the host. A number of cytokines (table 1) and small-molecule mediators can dampen the immune response.

Prostaglandins (such as prostaglandin E2) produced by macrophages can inhibit a variety of functions, including the induction of human leukocyte antigen (HLA) DR on macrophages and the production of interferon (IFN) gamma by T cells [59].

Transforming growth factor (TGF) beta is a potent suppressor of T cell activation and can decrease T cell proliferation and cytokine production [60]. It also decreases the number of interleukin (IL) 1 receptors, thereby making cells less sensitive to other cytokines.

IL-10 deactivates macrophages, which in turn decreases production of cytokines by T cells [61].

IL-35 inhibits the amplification of T helper cell type 17 (Th17) cells [62].

These control mechanisms are critical elements for keeping the inflammatory response in check and maintaining homeostasis. Their importance can be demonstrated in animals that lack some of these elements. As an example, rodents that lack the TGF-beta gene have a generalized inflammatory disease due to the absence of its suppressive influence [63]. This observation illustrates that cytokines are as important to the termination of the immune response as they are to its initiation.

Gamma-delta T cells — T cells expressing the gamma-delta (TCR1) form of the TCR are a distinct functional class whose physiologic role is not yet understood. In normal individuals, approximately 1 to 5 percent of circulating T cells are TCR1+, the great majority of these cells are "double negative" (DN or CD4-CD8-) [64]. As in blood, the TCR1/TCR2 ratio is approximately 1 in 50 in secondary lymphoid tissues. However, in other locations, such as gut epithelium, the ratio is 1 in 5. (See "Normal B and T lymphocyte development".)

Gamma-delta T cells have the capacity to interact with a variety of low-molecular-weight alkyl phosphates [64]. Many such compounds are found in mycobacterial cytoplasm. Alkylamines also stimulate gamma-delta T cells. The restricting elements for gamma-delta T cell antigen recognition are generally not classic MHC antigens but nonclassic MHC class I-like molecules, such as CD1, Qa, TL, or the MHC class I chain-related genes MICA and B (the latter via natural killer group 2 D [NKG2D]) [48,64].

Although gamma-delta cells may be stimulated by dendritic cells (DCs) and other professional APCs, their ability to interact with nonclassic MHC class I molecules may permit them to respond to antigens in situ when presented by other types of cells, such as intestinal enterocytes. The requirements for costimulation for gamma-delta cell activation are not yet clear. Some gamma-delta cells express CD28, but other mechanisms may operate in CD28-negative populations.

TCR1+ T cells are expanded in a variety of infections, such as tuberculosis, leprosy, malaria, toxoplasmosis, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and Lyme disease [64]. In some murine models, this activity cannot be completely compensated by TCR2+ cells. This has not been clearly shown for humans. TCR1+ T cells are speculated to have some role in modulating or limiting inflammation initiated by TCR2+ T cells. Gamma-delta T cells do not appear to contribute to the memory T cell pool.

Gamma-delta T cells having phenotypes similar to T helper cell type 1 (Th1), T helper cell type 2 (Th2), and cytotoxic and regulatory T cells (Tregs) have all been described [64]. In some cases, these cells are CD4 or CD8 positive, indicating that they are not generally representative of TCR1+ cells. On the other hand, some are the more common DN type. Some have speculated that TCR1+ T cells are a more primitive form of cellular immunity and that they represent a "first line of defense" during infection. Much remains to be learned regarding the physiologic role(s) of gamma-delta T cells.

Natural killer T cells — Natural killer T (NKT) cells are characterized by the surface expression of a single antigen receptor with an invariant V-J segment that recognizes glycolipids in combination with CD1d, an MHC I-like molecule. These cells express either CD4 or are negative for both CD4 and CD8. NKT cells are found in the thymus, spleen, liver, and bone marrow. Binding of NKT cells to the target antigen typically leads to IFN-gamma production, which in turn can upregulate NK and CD8 T cell activity. This combined adjuvant action has led to consideration for application of NKT cells in the treatment of advanced malignancies due to the ability to enhance destruction of malignant cells that do and do not express MHC I [65,66].


Cell-mediated immunity – T cells are the effectors of antigen-specific cell-mediated immunity (CMI). CMI is important in the elimination of cells infected with pathogens that replicate intracellularly (eg, viruses, mycobacteria, and some bacteria) and cells exhibiting aberrant differentiation (eg, neoplasms). CMI also destroys allogeneic cells (graft rejection). In addition, it is involved in cellular autoimmune responses, as well as type IV allergic reactions to drugs and contact dermatitis. (See 'Introduction' above.)

Response initiation by APCs – T cell responses are initiated by antigen-presenting cells (APCs), primarily dendritic cells (DCs). (See 'Antigen-presenting cells' above.)

Two-signal activation – T cell activation is thought to occur via a two-signal model. Signal 1 derives from contact of the T cell receptor (TCR)-CD3 complex with a major histocompatibility complex (MHC)-peptide complex. Signal 2 derives from costimulatory pathways. (See 'T cell activation and functions' above.)

Helper T cells – Helper T (Th) cells may be subdivided into effector populations with distinct cytokine secretion profiles (figure 3 and table 1). (See 'Cytokine profiles and functions of CD4+ T helper cell subsets' above and 'Cytokines' above.)

Cytotoxic T cells – Most cytotoxic T lymphocytes (CTLs) express the alpha-beta TCR heterodimer with the CD8 molecule and recognize peptide antigens in association with MHC class I. These cells kill target cells by two principal mechanisms: exocytosis of cytolytic granules containing perforin, granzymes, and other cytotoxic molecules and the interaction of Fas ligand (FasL) on CTLs with Fas expressed on target cells. (See 'Cytotoxic T lymphocyte function' above.)

T cell regulation – T cells are critical in the regulation of both humoral (antibody) and cellular effector mechanisms. Antibody responses to most protein and glycoprotein antigens require T cell help. Regulatory T cells (Tregs) also control specific cellular cytotoxicity. T cell regulation is mediated by cellular contacts and soluble factors. The cellular immune response can be amplified through positive feedback loops or dampened through negative regulation. (See 'Cellular regulation of immune responses' above.)

Gamma-delta T cells – Most gamma-delta T cells do not express either CD4 or CD8. However, they can be divided into functional subsets similar to helper, cytotoxic, and regulatory T cells that express the alpha-beta receptor. The ligands for gamma-delta TCRs in most cases are not peptide MHC complexes but rather pathogen-associated molecules that interact by different mechanisms with MHC-like molecules. (See 'Gamma-delta T cells' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, who contributed as an author to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 3980 Version 18.0


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