T cells proliferate vigorously following acute depletion of CD4 + Foxp3 + T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1 − /− hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies.
|Number of pages||10|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2019 Jan 15|
Bibliographical noteFunding Information:
aAcademy of Immunology and Microbiology, Institute for Basic Science, Pohang 37673, Republic of Korea; bDepartment of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, Republic of Korea; cImmunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; dSt. Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia; and eDivision of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
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