. Dysbiosis (gut microbiota imbalance) has been implicated in gut-distal autoimmune diseases, such as autoimmune arthritis and lupus.!However, the mechanisms by which gut microbiota impact gut-distal/systemic diseases remain largely unknown. T follicular helper (Tfh) cells specialize in helping B cells, and excessive Tfh responses put patients at risk for autoimmunity. Previously, using the K/BxN autoimmune arthritis model, we showed that gut commensal segmented filamentous bacteria (SFB) induce arthritis by driving differentiation and egression of Peyer's patch (PP) Tfh cells into systemic sites, boosting systemic Tfh responses and exacerbating arthritis. SFB induce PP Tfh differentiation by limiting IL-2 access to CD4+ T cells, thereby enhancing Bcl-6, the Tfh cell master regulator, in a dendritic cell (DC)-dependent manner. Notably, many autoimmune patients exhibit IL-2 deficiency, and low-dose IL-2 provides promising autoimmune therapy. We will determine how microbiota-mediated IL-2 deficiency affects both Tfh-related autoimmunity and IL-2 therapy (Aim 1). We will first examine whether Tfh cell induction by SFB relies on CD25-expressing DCs, quenching IL-2 secreted by CD4+ T cells at the T-B cell border. We will track single cell migration between gut and systemic sites and identify circulating Tfh cells as well as peripheral helper T (Tph) cells, a new cell type found in RA that also helps B cells, in blood as a potential biomarker for dysbiosis-induced autoimmunity in our mouse model and patients with rheumatoid arthritis (RA). We reported that SFB promote K/BxN autoimmunity by inducing dual TCR-expressing Th17 cells. Our new data also show the presence of IL-17+ Tfh-like cells in SFB+ K/BxN mice. We hypothesize that microbiota promote the conversion of Th17 into Tfh cells in PPs, which enhances autoimmune arthritis (Aim 2). We will examine plasticity by Th17 fate mapping and use single cell TCR analysis to analyze if a microbiota-skewed dual TCR repertoire promotes autoimmunity. We will use the Cre-loxP system to address the function of Th17-derived Tfh cells. Chronic antigen (Ag) exposure causes T cell exhaustion. Autoimmune T cells also encounter chronic Ag, but the role of exhaustion in autoimmunity is less clear. Prolonged IL-2 exposure induces Blimp-1 and depletes cellular glucose to promote T cell exhaustion, which is countered by Bcl-6. As SFB reduce IL-2 signaling and induce Bcl-6, we theorize that microbiota trigger autoimmunity by inhibiting T and/or Tfh cell exhaustion (Aim 3). We will ablate exhaustion marker Tim-3 to study exhaustion's contribution to autoimmunity. We will examine if IL-2 and microbiota inversely control Tfh glycolysis to modulate T cell exhaustion. We will also test if gut-derived Tfh and Tph cells are less exhausted and have increased cellular glucose in human RA. In conclusion, we will learn how microbiota induce gut-distal diseases by altering gut Tfh cell plasticity and exhaustion. We expect IL-2 therapy works by inhibiting Tfh cells, and that cTfh and Tph cells may serve as a dysbiotic autoimmune signal. This proposal is unique as it focuses on mucosal immunity and its link to systemic autoimmunity. !

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 Tfh cells, a T cell type specializing in B cell help. We will examine how microbiota inhibit IL-2 signaling to modulate Tfh-related autoimmunity and autoimmune therapies; we will also test the hypothesis that microbiota trigger autoimmunity by modulating Th17 to Tfh cell plasticity (the ability of one T cell type to reprogram into another T cell type) and T and/or Tfh exhaustion (T cell dysfunction due to prolonged antigen exposure). 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, which have been 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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Peyman, John A
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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