CD11c + T-bet + B cells generated during ehrlichial infection require CD4 + T cell help and IL-21 signaling for their development, but the exact T cell subset required had not been known. In this study, we show in a mouse model of Ehrlichia muris that type 1 T follicular helper (T FH1 ) cells provide help to CD11c + T-bet + B cells via the dual secretion of IL-21 and IFN-g in a CD40/CD40Ldependent manner. T FH1 cell help was delivered in two phases: IFN-g signals were provided early in infection, whereas CD40/ CD40L help was provided late in infection. In contrast to T-bet + T cells, T-bet + B cells did not develop in the absence of B cellintrinsic Bcl-6 but were generated in the absence of T-bet. T-bet-deficient memory B cells were largely indistinguishable from their wild-type counterparts, although they no longer underwent switching to IgG2c. These data suggest that a primary function of T-bet in B cells during ehrlichial infection is to promote appropriate class switching, not lineage specification. Thus, CD11c + memory B cells develop normally without T-bet but require Bcl-6 and specialized help from dual cytokine-producing T FH1 cells.
Bacterial, parasitic, and viral infections are well-known causes of lymphoid tissue disorganization, although the factors, both host and/or pathogen derived, that mediate these changes are largely unknown. Ehrlichia muris infection in mice causes a loss of germinal center (GC) B cells that is accompanied by the generation of extrafollicular T-bet + CD11c + plasmablasts and IgM memory B cells. We addressed a possible role for TNF-a in this process because this cytokine has been shown to regulate GC development. Ablation of TNF-a during infection resulted in an 8-fold expansion of GL7 + CD38 lo CD95 + GC B cells, and a 2.5-and 5-fold expansion of CD138 + plasmablasts and T-bet + memory cells, respectively. These changes were accompanied by a reduction in splenomegaly, more organized T and B cell zones, and an improved response to Ag challenge. CXCL13, the ligand for CXCR5, was detected at 6-fold higher levels following infection but was much reduced following TNF-a ablation, suggesting that CXCL13 dysregulation also contributes to loss of lymphoid tissue organization. T follicular helper cells, which also underwent expansion in infected TNF-a-deficient mice, may also have contributed to the expansion of T-bet + B cells, as the latter are known to require T cell help. Our findings contrast with previously described roles for TNF-a in GCs and reveal how host-pathogen interactions can induce profound changes in cytokine and chemokine production that can alter lymphoid tissue organization, GC B cell development, and extrafollicular T-bet + B cell generation.
The sex-bias of disease susceptibility has remained a puzzling aspect of several autoimmune conditions, including post-infection viral autoimmunity. In the last half of the twentieth century, the incidence rate of female-biased autoimmunity has steadily increased independent of medical advances. This has suggested a role for environmental factors, such as endocrine disrupting chemicals, which have been described to interfere with endocrine signaling. Endocrine involvement in the proper function of innate and adaptive immunity has also been defined, however, these two areas have rarely been reviewed in correlation. In addition, studies addressing the effects of endocrine disruptors have reported findings resulting from a broad range of exposure doses, schedules and models. This experimental heterogeneity adds confusion and may mislead the translation of findings to human health. Our work will normalize results across experiments and provide a necessary summary relevant to human exposure. Through a novel approach, we describe how different categories of ubiquitously used environmental endocrine disruptors interfere with immune relevant endocrine signaling and contribute to autoimmunity. We hope this review will guide identification of mechanisms and concentration-dependent EDC effects important not only for the sex-bias of autoimmunity, but also for other conditions of immune dysfunction, including post-infection autoreactivity such as may arise following severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, Herpes Simplex virus.
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