Xenogeneic beta sub(2)-Microglobulin Substitution Affects Functional Binding of MHC Class I Molecules by CD8 super(+) T Cells

• Published in: Journal of Immunology 2007-09, Vol.179 (6), p.3588-3595
• Main Authors: Benoit, Loralyn A, Tan, Rusung
• Format: Article
• Language: English
• ISSN: 0022-1767; 1365-2567

NK cells and CD8 super(+) T cells bind MHC-I molecules using distinct topological interactions. Specifically, murine NK inhibitory receptors bind MHC-I molecules at both the MHC-I H chain regions and beta sub(2)-microglobulin ( beta sub(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 sub(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 sub(2)m to modify the interaction between TCR and MHC-I. Using a human beta sub(2)m-transgenic C57BL/6 mouse model, we show that human beta sub(2)m supports formation and expression of H-2K super(b) and peptide:H-2K super(b) complexes at levels nearly equivalent to those in wild-type mice. Despite this finding, the frequencies of CD8 super(+) single-positive thymocytes in the thymus and mature CD8 super(+) T cells in the periphery were significantly reduced and the TCR V beta repertoire of peripheral CD8 super(+) T cells was skewed in the human beta sub(2)m-transgenic mice. Furthermore, the ability of mouse beta sub(2)m-restricted CTL to functionally recognize human beta sub(2)m super(+) target cells was diminished compared with their ability to recognize mouse beta sub(2)m super(+) 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-I molecule. Our results indicate that alterations in beta sub(2)m influence the ability of TCR to engage MHC-I during normal T cell physiology.