Xenogeneic beta 2-microglobulin substitution affects functional binding of MHC class I molecules by CD8+ T cells.
NK cells and CD8+ 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 beta2-microglobulin (beta2m) while TCR engages MHC-I molecules at a region defined solely by the class I H chain and bound peptide. As such, alterations in beta2m are not predicted to influence functional recognition of MHC-I by TCR. We have tested this hypothesis by assessing the capability of xenogeneic beta2m to modify the interaction between TCR and MHC-I. Using a human beta2m-transgenic C57BL/6 mouse model, we show that human beta2m 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 Vbeta repertoire of peripheral CD8+ T cells was skewed in the human beta2m-transgenic mice. Furthermore, the ability of mouse beta2m-restricted CTL to functionally recognize human beta2m+ target cells was diminished compared with their ability to recognize mouse beta2m+ 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 beta2m influence the ability of TCR to engage MHC-I during normal T cell physiology.
Benoit
Loralyn A
LA
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Tan
Rusung
R
D019943:Amino Acid Substitution / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D015478:Antigens, Heterophile / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D004527:Egg Proteins / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*