Xenogeneic β2-Microglobulin Substitution Affects Functional Binding of MHC Class I Molecules by CD8+ T Cells

NK cells and CD8(+) T cells bind MHC-1 molecules using distinct topological interactions. Specifically, murine NK inhibitory receptors bind MHC-1 molecules at both the MHC-1 H chain regions and beta(2)-microglobulin (beta(2)m) while TCR engages MHC-I molecules at a region defined solely by the class I H chain and bound peptide. As such, alterations in beta(2)m are not predicted to influence functional recognition of MHC-I by TCR. We have tested this hypothesis by assessing the capability of xenogeneic beta(2)m to modify the interaction between TCR and MHC-1. Using a human beta(2)m-transgenic C57BL/6 mouse model, we show that human beta(2)m supports formation and expression of H-2K(b) and peptide:H-2K(b) complexes at levels nearly equivalent to those in wild-type mice. Despite this finding, the frequencies of CD8(+) single-positive thymocytes in the thymus and mature CD8(+) T cells in the periphery were significantly reduced and the TCR V beta repertoire of peripheral CD8(+) T cells was skewed in the human beta(2)m-transgenic mice. Furthermore, the ability of mouse beta(2)m-restricted CTL to functionally recognize human beta(2)m(+) target cells was diminished compared with their ability to recognize mouse beta(2)m(+) target cells. Finally, we provide evidence that this effect is achieved through subtle conformational changes occurring in the distal, peptide-binding region of the MHC-1 molecule. Our results indicate that alterations in beta(2)m influence the ability of TCR to engage MHC-I during normal T cell physiology.