cytotoxic T cells (CTL) requires interaction with HLA class I polymorphisms, such engagement turns natural killer (NK) cells off. These contrasting mechanisms give complementarily to NK and CTL responses. The overall goal of this research is to understand the interaction of human T-cell receptors and NK cell receptors with HLA class I, and the modulation in specificity and function caused by natural HLA polymorphism. Investigation is focused on HLA-B, the locus most clearly implicated in both CTL and NK function.
Aim 1 determines the effects that polymorphisms within the diverse family of HLA-B15 allotypes have upon peptide binding specificity, the repertoire of endogenous peptides bound and the stimulation of alloreactive CTL. One family member (B*4601) has an HLA-C derived motif, which causes it to interact with NK cell receptors like an HLA-C allotype and to have an unprecedented bias for binding 3 cellular peptides. The basis for these unusual properties will be determined.
Aim 2 will define the HLA class I determinants recognized by the NK cell receptors and the effects of HLA types on the NK cell repertoire. Through comparison of natural and mutant HLA-B allotypes the specificity of the NKB1 receptor, which correlates with the Bw4 serological epitope, will be determined. The role of bound peptide in creating the inhibitory determinant will be assessed. The expression of class I receptors by the NK cells and T cells of unrelated donors and family members with different HLA-A,B,C type will be compared. For selected donors, a panel of NK cell clones will be characterized for their specificity of class I inhibition and expression of class I receptors. Predictions of the 'Missing Self' model will be tested.
Aim 3 will determine the mechanism by which engagement of a receptor by a complementary class I ligand leads to 'turning off' of the NK cell. The 'Effector Inhibition' model will be tested. Pathways of signal transduction will be compared in NKB1+ NK cells confronted with target cells expressing either Bw4+ or Bw4- HLA-B molecules. Changes found in tyrosine phosphorylation provide one basis for further study. The effects of class I engagement on Fc receptor mediated lysis and cytokine secretion, and of cross-linking the NKB1 receptor with specific antibody will be studied. Comparison of NK cells and alloreactive CTL responding to the same class I allotype will be made. In sum, the three aims will increase knowledge of the manner by which HLA class I polymorphisms control and individualize the cytolytic response to allogeneic transplants and cells compromised by virus infection or malignant transformation.
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