Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells
Total Page：16
File Type：pdf, Size：1020Kb
Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses Reza Nadafi, Catarina Gago de Graça, Eelco Keuning, Jasper Koning, Sander de Kivit, Tanja Konijn, Sandrine Henri, Jannie Borst, Rogier Reijmers, Lisa G.M. van Baarsen, et al. To cite this version: Reza Nadafi, Catarina Gago de Graça, Eelco Keuning, Jasper Koning, Sander de Kivit, etal.. Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autore- active T and B Cell Responses. Cell Reports, Elsevier Inc, 2020, 30 (12), pp.4110-4123.e4. 10.1016/j.celrep.2020.03.007. hal-02982506 HAL Id: hal-02982506 https://hal.archives-ouvertes.fr/hal-02982506 Submitted on 21 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Article Lymph Node Stromal Cells Generate Antigen- Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses Graphical Abstract Authors Reza Nadafi, Catarina Gago de Grac¸a, Eelco D. Keuning, ..., Rogier M. Reijmers, Lisa G.M. van Baarsen, Reina E. Mebius Correspondence [email protected] In Brief Lymph node stromal cells influence adaptive immune cells in various ways. Nadafi et al. show that by presenting self- antigens on MHC class II, lymph node stromal cells promote the differentiation of CD4+ T cells into regulatory T cells, which are able to prevent the generation of follicular T helper cells and germinal center B cells directed against the same self-antigen. Highlights d Lymph node stromal cells convert naive CD4+ T cells into TREG cells d Conversion of TREG cells by lymph node stromal cells is IL-2 dependent d Autoreactive TFH cells and B cells are controlled by lymph node stromal cells Nadafi et al., 2020, Cell Reports 30, 4110–4123 March 24, 2020 ª 2020 The Author(s). https://doi.org/10.1016/j.celrep.2020.03.007 Cell Reports Article Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses Reza Nadafi,1,2 Catarina Gago de Grac¸a,1 Eelco D. Keuning,1 Jasper J. Koning,1 Sander de Kivit,2,3 Tanja Konijn,1 Sandrine Henri,4 Jannie Borst,2,3 Rogier M. Reijmers,1,7 Lisa G.M. van Baarsen,5,6 and Reina E. Mebius1,8,* 1Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, the Netherlands 2Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands 3Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands 4Centre d’Immunologie de Marseille-Luminy, Aix Marseille Universite, INSERM, CNRS, 13288 Marseille, France 5Department of Rheumatology and Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC and University of Amsterdam, Amsterdam, the Netherlands 6Amsterdam Rheumatology and Immunology Center (ARC), Academic Medical Center, Amsterdam, the Netherlands 7Present address: LUMICKS, Pilotenstraat 41, Amsterdam, the Netherlands 8Lead Contact *Correspondence: [email protected] https://doi.org/10.1016/j.celrep.2020.03.007 SUMMARY the development of a broad range of autoimmune diseases such as juvenile dermatomyositis (Morita et al., 2011), Sjogren’s Within lymph nodes (LNs), T follicular helper (TFH) syndrome (Simpson et al., 2010; Szabo et al., 2013), systemic cells help B cells to produce antibodies, which can lupus erythematous (He et al., 2013; Simpson et al., 2010), and either be protective or autoreactive. Here, we rheumatoid arthritis (Arroyo-Villa et al., 2014; Ma et al., 2012; demonstrate that murine LN stromal cells (LNSCs) Rao et al., 2017; Wang et al., 2013; Zhang et al., 2015). TFH cells differentiate within the T cell area of lymph nodes (LNs) and are suppress the formation of autoreactive TFH cells in an antigen-specific manner, thereby significantly identified by the expression of Cxcr5, PD-1, and Bcl6 (Crotty, 2014). Bcl6 is an essential transcription factor for their develop- reducing germinal center B cell responses directed ment, while expression of chemokine receptor Cxcr5 guides TFH against the same self-antigen. Mechanistically, cell migration to B cell follicles, where they contribute to the LNSCs express and present self-antigens in major maturation and differentiation of B cells (Crotty, 2014). histocompatibility complex (MHC) class II, leading Regulatory pathways need to be in place to control the forma- + to the conversion of naive CD4 T cells into T regula- tion and development of autoreactive TFH cells. Among diverse tory (TREG) cells in an interleukin-2 (IL-2)-dependent regulatory mechanisms, it is particularly important to mention manner. Upon blockade of TREG cells, using neutral- the fundamental role of T regulatory (TREG) cells in preventing izing IL-2 antibodies, autoreactive TFH cells are autoreactive T cell formation in the thymus and periphery (Jose- allowed to develop. We conclude that the continuous fowicz et al., 2012). Generation of TREG cells in the thymus is the presentation of self-antigens by LNSCs is critical to result of the recognition of self-antigens by T cells bearing a high- generate antigen-specific T cells, thereby repres- affinity T cell receptor (TCR) (Jordan et al., 2001). Expression of REG the vast majority of self-antigens in the thymus is restricted to sing the formation of T cells and germinal center B FH a unique non-hematopoietic stromal cell population known as cell responses. Our findings uncover the ability of medullary thymic epithelial cells (mTECs), which are able to steer LNSCs to suppress the early activation of autoreac- the differentiation of CD4+ T cells with high-affinity TCRs into + tive immune cells and maintain peripheral tolerance. FoxP3 TREG cells (Anderson et al., 2002; Aschenbrenner et al., 2007; Derbinski et al., 2001; Hinterberger et al., 2010). The INTRODUCTION expression and presentation of self-antigens, however, is not limited to mTECs in the thymus, as several LN stromal cell Autoimmunity emerges when immune tolerance against self-an- (LNSC) subsets— including fibroblastic reticular cells (FRCs), tigens is lost. As a result, the recognition of self-antigens by cells lymphatic endothelial cells (LECs), blood endothelial cells of the adaptive immune system leads to the formation and devel- (BECs), and double-negative (DN) cells—also display unique opment of autoreactive B cells in germinal centers (GCs) and expression patterns of self-antigens (Cohen et al., 2010; Fletcher autoantibody production (Yanaba et al., 2008). T follicular helper et al., 2010; Nichols et al., 2007). The effect of self-antigen pre- (TFH) cells are speculated to be the central players in the sentation by LNSCs on autoreactive T cells has been shown in pathogenesis of autoimmune diseases by steering a selective various studies (Cohen et al., 2010; Dubrot et al., 2014; Fletcher expansion of high-affinity autoreactive B cells in GCs (Craft, et al., 2010; Lee et al., 2007; Magnusson et al., 2008; Nichols 2012). Accordingly, alterations in TFH cells are associated with et al., 2007; Rouhani et al., 2015), suggesting that the process 4110 Cell Reports 30, 4110–4123, March 24, 2020 ª 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Figure 1. Antigen-Specific TREG Cell Conversion Occurs in the Lymph Nodes 6 (A) In vivo experimental design to study TREG cell conversion in LNs. WT C57L/6J and K14-mOva mice were intravenously injected with 5–8 3 10 CFSE-labeled CD4+ OT-II.Rag2À/À T cells. 1 and 3 days after CD4+ T cell transfer, mice were sacrificed, and LNs were isolated for analysis of transferred CD4+ OT-II.Rag2À/À T cells by flow cytometry (B and C) and immunofluorescence (D and E). (B) Representative contour plots of live CFSE-labeled CD4+CD3+ OT-II.Rag2À/À T cells in peripheral LNs, in which the numbers in the plots display the frequency + + of CD25 FoxP3 TREG cells. (legend continued on next page) Cell Reports 30, 4110–4123, March 24, 2020 4111 of peripheral tolerance is necessary to further complete TREG cell the contribution of LNSCs in TREG cell conversion in vivo, naive generation in the thymus. carboxyfluorescein succinimidyl ester (CFSE)-labeled CD4+ Recently, we have demonstrated that LNSCs constrain T cells from OT-II.Rag2À/À, which lack endogenous thymic + + immune reactivity via presentation of self-antigens in major his- CD25 FoxP3 TREG cells (Figure S1B), were intravenously in- tocompatibility complex (MHC) class II, which results in the jected into wild-type (WT) C57BL/6J and K14-mOva mice. LNs + selective maintenance of antigen-specific TREG cells (Baptista were isolated 1 and 3 days after the CFSE-labeled CD4 T cell et al., 2014). The expression of MHC class II by LNSCs and not transfer (Figure 1A). Analysis of peripheral (axillary, brachial, dendritic cells (DCs) was shown to be critical to preventing the inguinal, and popliteal) LNs at day 3 showed that Ova-specific activation of both CD4+ and CD8+ cells (Baptista et al., 2014; TCR-transgenic CD4+CD3+ OT-II.Rag2À/À T cells converted + + Dubrot et al., 2018). Nevertheless, the question of whether into CD25 FoxP3 TREG cells solely in K14-mOva LNs, wherein self-antigen presentation by LNSCs may in fact induce anti- Ova is exclusively expressed as a self-antigen by LNSCs.