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Unexpected role for MHC II–peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo

Do, Jeong-su, Valujskikh, Anna, Vignali, Dario A. A., Fairchild, Robert L., Min, Booki
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.31 pp. 12698-12703
CD8-positive T-lymphocytes, cytokines, homeostasis, immune response, inflammation, mice, peptides, thymocytes
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.