김선정 (Feinstein Institute for Medical Research) | 한빛사논문 > 한빛사

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조회166

Feinstein Institute for Medical Research

Proc. Natl. Acad. Sci. USA, Nov 28 2023, 120 (48) | https://doi.org/10.1073/pnas.2309780120 Peripheral T cell activation, not thymic selection, expands the T follicular helper repertoire in a lupus-prone murine model

Kyungwoo Lee^a,b,1, Juyeon Park^c,1, Hidetaka Tanno^d,e, George Georgiou^d, Betty Diamond^a,f,2,3, and Sun Jung Kim^a,f,3

^aCenter for Autoimmune, Musculoskeletal and Hematopoietic Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030;

^bDepartment of Biology, Hofstra University, Hempstead, NY 11549;

^cDepartment of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712;

^dDepartment of Chemical Engineering, University of Texas at Austin, Austin, TX 78712;

^eCancer Immunology Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156- 8506, Japan; and

^fDepartment of Molecular Medicine, Northwell Health- Hofstra School of Medicine, Hofstra University, Hempstead, NY 11549

¹K.L. and J.P. contributed equally to this work.

²To whom correspondence may be addressed.: Betty Diamond

³B.D. and S.J.K. contributed equally to this work.

Abstract

Many autoimmune diseases are characterized by the activation of autoreactive T cells. The T cell repertoire is established in the thymus; it remains uncertain whether the presence of disease-associated autoreactive T cells reflects abnormal T cell selection in the thymus or aberrant T cell activation in the periphery. Here, we describe T cell selection, activation, and T cell repertoire diversity in female mice deficient for B lymphocyte-induced maturation protein (BLIMP)-1 in dendritic cells (DCs) (Prdm1 CKO). These mice exhibit a lupus-like phenotype with an expanded population of T follicular helper (Tfh) cells having a more diverse T cell receptor (TCR) repertoire than wild-type mice and, in turn, develop a lupus-like pathology. To understand the origin of the aberrant Tfh population, we analyzed the TCR repertoire of thymocytes and naive CD4 T cells from Prdm1 CKO mice. We show that early development and selection of T cells in the thymus are not affected. Importantly, however, we observed increased TCR signal strength and increased proliferation of naive T cells cultured in vitro with antigen and BLIMP1-deficient DCs compared to control DCs. Moreover, there was increased diversity in the TCR repertoire in naive CD4+ T cells stimulated in vitro with BLIMP1-deficient DCs. Collectively, our data indicate that lowering the threshold for peripheral T cell activation without altering thymic selection and naive T cell TCR repertoire leads to an expanded repertoire of antigen-activated T cells and impairs peripheral T cell tolerance.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2024-03-07)
연구진국외 연구진
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