THE HLA SYSTEM, ANTIGEN-PROCESSING AND PRESENTATION

Human leukocyte antigens (HLA) restrict immune responses by binding an tigenic peptides and presenting them in the context of self to T lymph ocytes. In transplantation, a vigorous T cell response, termed allorea ctivity, is caused by recognition of nun-self HLA. The major histocomp atibility complex (MHC) encodes two major classes of HLA molecules, de signated I and II. In general, HLA class I molecules present peptides derived by proteolysis of intracellular proteins (the endogenous pathw ay), while HLA class II molecules present peptides sampled from the ex tracellular body fluids (the exogenous pathway). The dichotomy between class I and class II antigens is reflected in the T cells in that the CDS cell surface glycoprotein is expressed by cytotoxic T lymphocytes and recognizes HLA class I, while CD4 is expressed on helper T cells and recognizes HLA class II. Although the two classes of HLA molecules are thought to have originated from a common ancestral gene, they hav e evolved specific structures and intracellular trafficking compartmen ts that account for their functions. The class I proteins bind short p eptides of right to nine amino acids that are tightly anchored at thei r ends. The class II proteins bind longer peptides that are more heter ogeneous in size (12 to 28 amino acids) and have ragged ends. The clas s I peptides are generated by proteasomes and other mechanisms in the cytosol and translocated from the cytosol into the endoplasmic reticul um (ER). In the ER, functional HLA class I complexes are formed and th en transported to the cell surface for presentation. HLA class II mole cules are assembled without antigenic peptide. An ''invariant chain'' promotes the assembly of the class II molecule and protects its groove from binding peptides in the ER. In an endosomal compartment, antigen s that have entered the cell via pinocytosis or via receptor-mediated internalization are processed, the invariant chain is degraded, and an tigenic peptides bind to the HLA class II molecule. This mature comple x is transported to the cell surface for presentation. Alloreactivity is the special case of antigen presentation responsible for transplant rejection.