The HLA system, antigen processing and presentation

Human leukocyte antigens (HLA) restrict immune responses by binding antigenic peptides and presenting them in the context of self to T lymphocytes. In transplantation, a vigorous T cell response, termed alloreactivity, is caused by recognition of non-self HLA. The major histocompatibility complex (MHC) encodes two major classes of HLA molecules, designated I and II. In general, HLA class I molecules present peptides derived by proteolysis of intracellular proteins (the endogenous pathway), while HLA class II molecules present peptides sampled from the extracellular body fluids (the exogenous pathway). The dichotomy between class I and class II antigens is reflected in the T cells in that the CD8 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 have evolved specific structures and intracellular trafficking compartments that account for their functions. The class I proteins bind short peptides of eight to nine amino acids that are tightly anchored at their ends. The class II proteins bind longer peptides that are more heterogeneous in size (12 to 28 amino acids) and have ragged ends. The class I peptides are generated by proteasomes and other mechanisms in the cytosol and translocated from the cytosol into the endoplasmic reticulum (ER). In the ER, functional HLA class I complexes are formed and then transported to the cell surface for presentation. HLA class II molecules 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, antigens that have entered the cell via pinocytosis or via receptor-mediated internalization are processed, the invariant chain is degraded, and antigenic peptides bind to the HLA class II molecule. This mature complex is transported to the cell surface for presentation. Alloreactivity is the special case of antigen presentation responsible for transplant rejection.