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.
Bibliographical noteFunding 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.).