Schematic representation showing direct and indirect allorecognition during graft rejection

T cell recognition of alloantigen occurs by one of two separate pathways. T cell activation by the "direct" pathway occurs when T cells encounter intact donor MHC on the surface of donor antigen-presenting cells (APC). This pathway is thought to be of dominant importance during early acute rejection as engrafted organs contain a large number of passenger leukocytes. Intact donor MHC molecules are also known to be continuously shed into the circulation where they may then be endocytosed by the recipient's antigen-presenting cells. Within the acidic endosomal compartment, the MHC proteins are fragmented into their constituent peptides. They are then transferred into the endoplasmic reticulum, loaded into the antigen binding cleft of MHC class II of the recipient and finally expressed on the cell surface of recipients APCs. This mechanism has been referred to as the "indirect allorecognition." However, this is of course the normal route by which T cells normally encounter antigen.