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POSTECH, 기초과학연구원

Proc. Natl. Acad. Sci. USA, Published ahead of print December 31, 2018 | https://doi.org/10.1073/pnas.1818624116 Unregulated antigen-presenting cell activation by T cells breaks self tolerance

Jaeu Yi^a,b, Jisun Jung^a,b, Sung-Wook Hong^a,b, Jun Young Lee^a,b, Daehee Han^a,b, Kwang Soon Kim^a,b, Jonathan Sprent^c,d,1,2, and Charles D. Surh^a,b,e,1,3

^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

¹J.S. and C.D.S. contributed equally to this work.
²To whom correspondence should be addressed.
³Deceased October 6, 2017.

Abstract

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.

antigen-free mice, self tolerance, regulatory T cells, costimulatory molecules, autologous mixed lymphocyte reaction

논문정보

형식Research article
게재일2018년 12월 (BRIC 등록일 2019-01-11)
연구진국내(교신)+국외 연구진
분야 생명과학 > 면역학

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