CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors

Lokesh A. Kalekar, Shirdi E. Schmiel, Sarada L. Nandiwada, Wing Y. Lam, Laura O. Barsness, Na Zhang, Gretta L. Stritesky, Deepali Malhotra, Kristen E. Pauken, Jonathan L. Linehan, Gerard O'Sullivan, Brian T Fife, Kristin A Hogquist, Marc Jenkins, Daniel L Mueller

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4+ T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4+ T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4+ T cells was associated with hypomethylation of genes related to thymic regulatory T cells (T reg cells), and this correlated with their ability to differentiate into Foxp3 + T reg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral T reg cell differentiation.

Original languageEnglish (US)
Pages (from-to)304-314
Number of pages11
JournalNature immunology
Issue number3
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
We thank J.A. Bluestone (University of California, San Francisco) for spleen and lymph node cells from Foxp3-Cre-GFP × R26-YFP mice and discussions; D. Mathis and C. Benoist (Harvard Medical School) and the Institut de Genetique et de Biologie Moleculaire et Cellulaire (Strasbourg, France) for B6.g7 mice and KRN B6 mice; A. Rudensky (Memorial Sloan-Kettering Cancer Center) for B6 Foxp3DTR knock-in mice; S.S. Way (University of Cincinnati) for B6 Foxp3GFP and Foxp3DTR CD45.1 mice; J.A. Bluestone (University of San Francisco) for cells from the spleen and all lymph nodes of Foxp3-Cre-GFP × R26-YFP mice; S.C. Jameson, M. Mescher and M.A. Farrar for discussions; P.J. Titcombe for technical support; and N. Shah, T. Martin and J. Motl for assistance in cell sorting. Supported by the Rheumatology Research Foundation (Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign grant to D.L.M.) and the US National Institutes of Health (01 AI35296 to D.L.M., B.T.F., K.A.H. and M.K.J.).

Publisher Copyright:
© 2016 Nature America, Inc.


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