Abstract
CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4+ T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4+ T lymphocytes is induced by TGF-β1 and TGF-β3, which promote a pathogenic phenotype. In addition, CD70 is associated with a TH1 and TH17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70−/−CD4+ T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4+ T lymphocytes. CD70+CD4+ T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory TH1/TH17 lymphocytes infiltrating the CNS.
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Acknowledgements
T.D. holds a fellowship from the Fonds de Recherche du Québec-Santé (FRQS). L.T. holds scholarships from Université de Montréal and CRCHUM. E.P. holds a fellowship from the Multiple Sclerosis Society of Canada (MSSC) and the FRQS. S.Z. is supported by a fellowship from Biogen Canada. C.L. is supported by FRQS. A.P. holds the T1 (senior) Canada Research Chair in Multiple Sclerosis. This work was funded by operating grants from the Canadian Institutes of Health Research (MOP 89885, PJI-153195) and from the MSSC (EGID 2382). We thank Jannie Borst for providing us with the CD70−/− mice. We thank Hartmut Wekerle for providing us with the TCR1640 mice. Special thanks to Magdalena Paterka and Volker Siffrin for providing the protocol for CD4+ adoptive T cell transfer in RAG null mice. We would also like to thank the imaging platform, the pathology platform, and the flow cytometry platform from the CRCHUM for the excellent technical support and Alice M Roy and Elvia Gonzalez for their excellent technical animal support.
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T.D. and A.P. conceived, designed, and supervised the research, analyzed the data and wrote the paper. T.D., L.T., L.B., S.Z., E.P., C.L. and C.G. performed the experiments. X.A. and R.M.R. provided clinical information. J.P., B.L., P.D., M.G., R.M., A.P., C.L., and A.B. secured human blood, CSF, and brain samples. C.L., E.P., and S.Z. provided key scientific input.
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Dhaeze, T., Tremblay, L., Lachance, C. et al. CD70 defines a subset of proinflammatory and CNS-pathogenic TH1/TH17 lymphocytes and is overexpressed in multiple sclerosis. Cell Mol Immunol 16, 652–665 (2019). https://doi.org/10.1038/s41423-018-0198-5
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DOI: https://doi.org/10.1038/s41423-018-0198-5
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