Tcell Recognition Of

As noted previously, the principal function of HLA molecules is to acquire peptide fragments and to interact with effector T cells or NK cells. Peptide fragments bound by HLA molecules are found in a cleft whose walls are formed by more or less parallel alpha helices that sit atop a floor formed by p-pleated sheets (Figure 93.5). In class I molecules, six pockets are formed that accommodate side chains of the bound peptides.2025 Most of the highly polymorphic amino acid positions can be classified according to whether their side chains engage the bound peptide or the T-cell receptor (TCR) (contact residues).26 In a similar fashion, the peptide binding21,22 and TCR contact residues of class II mole cules have been addressed in crystallographic studies.27 While any HLA molecule can bind numerous different peptides, there is a selective or preferential binding of peptides (peptide binding motif) that is determined by the polymorphic HLA pocket residues. Since the TCR engages both bound peptide and TCR contact residues of the HLA molecule, T-cell specificity is influenced by both types of residues.

In HLA-identical transplants there are no foreign HLA molecules to which the donor can respond. However, cytotoxic T cells against minor histocompatibility antigens arise and can mediate GVHD and GVL.2829 In these cases, peptides from the minor his-tocompatibility antigens are bound by host HLA molecules and are presented to donor T cells. In essence, such T cells are responding to a foreign peptide in a "self" HLA molecule.

In an allogeneic response to a mismatched HLA antigen, a large portion of T cells are activated.30 While peptide-independent recognition of MHC has been demonstrated in some studies,3132 most alloreactive T cells would appear to recognize foreign MHC in a pep-tide-dependent or a peptide-specific fashion.33-38 Thus, despite most peptide-binding residues being inaccessible to TCRs, they can influence the T-cell response by

Figure 93.5 Peptide-binding structure of HLA class I molecules. This figure shows a representation of the peptide-binding structure formed by the a-1 and a-2 protein domains of a class I molecule. (a) Amino acid residues involved in peptide binding and (b) amino acid residues that contact the T-cell receptor. Residue positions in white are located in a-helical segments and those in black are located in fi-pleated sheet segments of the molecule. The indicated residues are those designated in Ref. 23 and/or 24

Figure 93.5 Peptide-binding structure of HLA class I molecules. This figure shows a representation of the peptide-binding structure formed by the a-1 and a-2 protein domains of a class I molecule. (a) Amino acid residues involved in peptide binding and (b) amino acid residues that contact the T-cell receptor. Residue positions in white are located in a-helical segments and those in black are located in fi-pleated sheet segments of the molecule. The indicated residues are those designated in Ref. 23 and/or 24

dictating which peptides are bound and their orientation by the foreign HLA molecules. Since T cells specific for foreign HLA plus peptides are not negatively selected during thymic selection, alloreactive T cells of this sort can represent a large fraction of the mature T-cell repertoire.

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