HLA class I gene polymorphism and functions

An important aspect of the HLA-A -B, and -C genes is their high level of polymorphism. Currently, over 80 alleles at the HLA-A locus, 185 at the HI.A-B locus, and 42 at the HLA-C locus have been defined. Comparison of sequences from a single locus shows the class I heavy chains are divided into a variable part comprising the al and «2 domains and a relatively conserved part consisting of a3, the transmembrane, and the cytoplasmic domains. The a 1 and «2 domains are known to bind diverse antigen peptides and form the site of interaction with variable T cell receptors. There are 20 amino acid positions with high variability, all in the al and a2 domains, which have been defined from a comparison of 39 HLA-A, -B and -C sequences. From the HLA-A2 structure, 47 residues were hypothesized to make contact with bound peptide, or to interact with the T cell receptor. Of the 20 residues of high variability, 19 residues are included in this group. In contrast, HLA-E, -F and -G genes show relatively little polymorphism.

The HLA-A, -B and -C antigens are the major antigens recognized by the host during tissue graft rejection. Cytotoxic T lymphocytes recognize viral antigens only in the context of a class I antigen. T lymphocytes elicited by such an exposure are restricted in their killing to the cells which bear the same class I antigens as were present on the sensitizing cells.

It has been postulated that HLA-C is a declining class I gene, since HLA-C has fewer alleles than HLA-A and HLA-B, differing by smaller numbers of substitutions which are frequently at positions not directly involved in contacting the bound peptide and the T cell receptor. In addition, there is much less HLA-C antigen than HLA-A and HLA-B antigen on the cell surface. However, HLA-C molecules are capable of antigen presentation, as demonstrated by experiments with transgenic mice. Whether there are sufficient HLA-C restricted T cells for this to happen with any frequency in the human immune response is a matter for question. All this evidence supports the idea that HLA-C contributes little to human immunity.

So far, no function has been assigned to HLA-E, -F and -G class I products, although it has been demonstrated that HLA-G is able to present peptides in a similar fashion to the classical class I molecules. Restriction of HLA-G expression to fetal extraembryonic tissue implies that HLA-G subserves a function critical to this tissue. Within the extraembryonic tissues, fetal cytotrophoblasts are exposed to the maternal decidua. It has been suggested that fetal trophoblasts function to shield the fetus from recognition by the maternal immune system. Clearly, the lack of HLA-A, -B and -C expression by these cells is consistent with such a function. Expression of the nonpolymorphic class I gene HLA-G should not result in fetal rejection by the maternal immune system, assuming the maternal immune system does not recognize HLA-G as foreign. It has been proposed that HLA-G may function to directly protect fetal cytotrophoblasts by activation of maternal suppressor cells or blockage of maternal cytotoxic cells.

HLA-G expression by fetal cytotrophoblasts may also function to enable the maternal immune system to survey these fetal cells, much as it does other maternal somatic cells. An immune surveillance capability seems warranted since fetal trophoblasr cells play a crucial role in the development of the embryo. HLA-G on the surface of fetal cytotrophoblasts could afford a mechanism by which an antigen is presented to the maternal immune system, for example, in case of a viral infection, while keeping the fetal cells from being seen as foreign by the maternal immune system. HI.A-G may have non-immunologic roles in modulating receptivity to soluble growth and differentiation molecules or it may be required for interplay with decidual cells.

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