TNF-α Contributes to Lymphoid Tissue Disorganization and Germinal Center B Cell Suppression during Intracellular Bacterial Infection

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-alpha in this process because this cytokine has been shown to regulate GC development. Ablation of TNF-alpha during infection resulted in an 8-fold expansion of GL7(+) CD38(1o) 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-alpha ablation, suggesting that CXCL13 dysregulation also contributes to loss of lymphoid tissue organization. T follicular helper cells, which also underwent expansion in infected TNF-alpha-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-alpha 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.