Unexpected role for MHC II-peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo.
Here we report a unique role for MHC II-peptide complexes in controlling immune responses of naïve CD8 T cells. Compared with CD8 T cells from WT mice, CD8 T cells isolated from MHC II(-/-) mice hyperproliferated under lymphopenic conditions, differentiated into effector cells producing proinflammatory cytokines, and mediated more severe tissue inflammation. The elevated responses of MHC II(-/-) CD8 T cells were due to the absence of MHC II, but not CD4, T cells. The hyperreactivity appeared to be a feature of mature T cells, given its absence in CD8 single positive thymocytes derived from MHC II(-/-) mice. Expression of the MHC II ligand LAG3 was markedly enhanced during in vivo activation of MHC II(-/-) CD8 T cells, and blockade of MHC II-LAG3 interactions further enhanced T-cell expansion. Importantly, CD8 T cells isolated from H-2M(-/-) mice expressing WT levels of MHC II also displayed hyperresponsiveness similar to that of MHC II(-/-) CD8 T cells, suggesting that peptides presented on MHC II are involved in the control of CD8 T-cell responses. Our results uncover a previously undefined MHC II-dependent regulation that tunes CD8 T-cell reactivity and may have implications for an improved understanding of CD8 T-cell homeostasis and functions.
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Jeong-su
JS
Do
Anna
A
Valujskikh
Dario A A
DA
Vignali
Robert L
RL
Fairchild
Booki
B
Min
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular; D051379:Mice; D018345:Mice, Knockout; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; C489628:H-2M antigen, mouse; D000949:Histocompatibility Antigens Class II; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse