Antigen presentation pathways and their role in human disease

T lymphocytes (T cells) have evolved to be the major effectors of cognate immunity in the vertebrate immune system. T cells possess receptors (TCRs) which, in a highly specific manner, recognize human leukocyte antigen (HLA)-presented peptides on the surface of host cells. HLA molecules bind peptides produced by degradation of proteins. The transporter associated with antigen processing (TAP) is a transmembrane protein responsible for the transport of antigenic peptides into the endoplasmic reticulum where they are then bind to HLA class I. The importance of TAP to the function of the HLA class I antigen presentation pathway is demonstrated by markedly reduced cell-surface HLA class I expression in cells defective in TAP expression (Spies & DeMars 1991). Understanding the pathways of antigen processing and presentation is important for the design ofimmunotherapeutic drugs and vaccines and for understanding the mechanism behind HLA-associated disease associations.

Analysis of the relationship between TAP binding affinity and HLA class I binding affinity across the full spectrum of HLA alleles is difficult because of the extensive polymorphism of HLA molecules. We addressed the problem by: (a) generating a computational model, (b) combining the initial model with a selected set of laboratory experiments for model refinement, and (c) using the refined model to analyse the functional relationship between TAP and HLA class I molecules (Daniel et al 1998). The working ANN model was used to search for patterns of TAP-binding within sets of HLA-binding peptides. The proportion of HLA-binding peptides with affinity to TAP varied for each HLA class I allele with a range of 15% for HLA-B*5401 to 100% for HLA-B*2703 (Brusic et al 1999). On the basis of these results we hypothesize that HLA alleles constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3 and -A24) and those that are TAP-inefficient (HLA-A2, -B7 and -B8). The strong similarity between the sets of peptides bound by TAP and HLA-B27 suggests close functional co-evolution. Advantages could include increased resistance to infection, cancers or autoimmunity at the individual or species level, but at the price of increased predisposition to ankylosing spondylitis. TAP-inefficient HLA alleles utilize TAP-independent peptide transport pathways to a greater degree. Evolutionary pressures may have selected TAP-inefficient HLA alleles to counter mechanisms evolved by pathogens to evade immune surveillance by blocking TAP-dependent peptide transport. The availability of computer-based models of TAP and HLA interaction is helpful in accelerating research into evolutionary relationships within the immune system as well as in designing more efficient human vaccines.

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