The gut microbiota has been implicated in many autoimmune diseases, both inside and outside the gut (gut- distal/systemic). However, how gut microbiota affects gut-distal diseases remains largely unknown. Notably, commensals have been reported to affect certain T cell subtype(s) including T helper 1 (Th1), Th17, and regulatory T cells (Tregs), but little is known about how or which commensals impact T follicular helper (Tfh) cells. Tfh cells are a crucial T cell type that helps B cells produce high-affinity antibodie (Abs) in the germinal center (GC). However, an overactive Tfh cell response can lead to autoimmunity. We have established a new and more physiologically relevant platform to study the commensal effect by introducing segmented filamentous bacteria (SFB) into specific-pathogen-free (rather than germ-free, our old approach) K/BxN autoimmune arthritis mice, whose disease mechanism relies on Tfh cells and auto-Abs. Our new data show that SFB strongly enhances disease in K/BxN mice and indicate a role for SFB in Tfh cells, as an increase in the Tfh and GC cell populations was observed in SFB (+) compared to SFB (-) K/BxN mice. To our knowledge, this is the first data to associate a specific commensal type with Tfh cells. Therefore, we hypothesize that gut microbiota can drive gut-distal autoimmune disease by enhancing the Tfh cell response. We will examine: 1) the mechanism for SFB-dependent expansion of systemic (splenic) Tfh cells and their significance in augmenting disease; 2) whether SFB boosts auto-Ab response by inducing Tfh cell cytokines, reprogramming other Th subtypes into Tfh cells, or directly acting on B cells; and 3) whether the gut can serve as a Tfh priming site, which is required for the systemic Tfh cell response. Specifically, we will address if SFB increases the number of Tfh cells by enhancing proliferation, survival, and/or differentiation. We will determine if Tfh cells are critical for SFB-mediated disease by using a K/BxN transfer model with CXCR5-/-KRN T cells, which are defective in mounting a Tfh response. We will use retroviral systems to see if overexpression of SFB- dependent cytokines can correct the defects in SFB (-) Tfh cells. We will test whether SFB can reprogram Th17 and Th2 cells into Tfh cells by adoptively transferring ex-vivo isolated Th17 or Th2 cells. We will use a transfer model with innate signaling-deficient MyD88-/- B cells to test if SFB can help B cells by acting directly on them through innate receptors. Our new data show a tremendous SFB-dependent increase in Tfh cells in the gut Peyer's patch (PP). Thus, we will examine the role of gut T cells in the splenic Tfh response by generating mice that lack T cells in gut-lymphoid-tissue (using transfer model with integrin 7-/-KRN T cells). Importantly, our latest data indicate strong significance and broad applications of this proposal, as the Tfh/GC enhancing effect of SFB found in the K/BxN model can also be demonstrated in NZB/NZW F1 mice, a natural and spontaneous lupus model. Studying the commensal effect on Tfh cells will have crucial impacts on public health, as dysbiosis caused by modern medical practice might trigger autoimmunity by affecting Tfh cells.

Public Health Relevance

This proposal will increase our understanding of a crucial but inadequately investigated scientific area: how gut commensal bacteria alter the development of a gut-distal (systemic) autoimmune disease by affecting the host's immunity. We will tackle this question by performing mechanistic studies on 1) how gut commensal bacteria can augment gut-distal autoimmunity by enhancing the response of T follicular helper cells, a key T subtype known to provide B cell help; 2) how the gut commensal-mediated intestinal immune response contributes to gut-distal autoimmunity. The results of these mechanistic studies will have crucial impacts on public health, as they will pave the way to generate novel immune- or microbe- based therapies for dysbiosis- related immune disorders that have being rising sharply in the industrialized world.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Rothermel, Annette L
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University of Arizona
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Felix, Krysta M; Jaimez, Ivan A; Nguyen, Thuy-Vi V et al. (2018) Gut Microbiota Contributes to Resistance Against Pneumococcal Pneumonia in Immunodeficient Rag-/- Mice. Front Cell Infect Microbiol 8:118
Felix, Krysta M; Tahsin, Shekha; Wu, Hsin-Jung Joyce (2018) Host-microbiota interplay in mediating immune disorders. Ann N Y Acad Sci 1417:57-70
Viladomiu, Monica; Kivolowitz, Charles; Abdulhamid, Ahmed et al. (2017) IgA-coated E. coli enriched in Crohn's disease spondyloarthritis promote TH17-dependent inflammation. Sci Transl Med 9:
Bradley, C Pierce; Teng, Fei; Felix, Krysta M et al. (2017) Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs. Cell Host Microbe 22:697-704.e4
Naskar, Debdut; Teng, Fei; Felix, Krysta M et al. (2017) Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses. J Immunol 198:1855-1864
Teng, Fei; Felix, Krysta M; Bradley, C Pierce et al. (2017) The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis. Arthritis Res Ther 19:188
Teng, Fei; Klinger, Christina N; Felix, Krysta M et al. (2016) Gut Microbiota Drive Autoimmune Arthritis by Promoting Differentiation and Migration of Peyer's Patch T Follicular Helper Cells. Immunity 44:875-88
Tan, Tze Guan; Sefik, Esen; Geva-Zatorsky, Naama et al. (2016) Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci U S A 113:E8141-E8150