Interactions between B cells and T follicular regulatory cells enhance susceptibility to Brucella infection independent of the anti-Brucella humoral response

Brucellosis, caused by facultative, intracellular Brucella spp., often results in chronic and/or lifelong infection. Therefore, Brucella must employ mechanisms to subvert adaptive immunity to cause chronic infection. B lymphocytes enhance susceptibility to infection with Brucella spp. though the mechanisms remain unclear. Here we investigated the role of antibody secretion, B cell receptor (BCR) specificity, and B cell antigen presentation on susceptibility to B. melitensis. We report that mice unable to secrete antibody do not display altered resistance to Brucella. However, animals with B cells that are unable to recognize Brucella through their BCR are resistant to infection. In addition, B cell MHCII expression enhances susceptibility to infection in a CD4(+) T cell-dependent manner, and we found that follicular B cells are sufficient to inhibit CD4(+) T cell-mediated immunity against Brucella. B cells promote development of T follicular helper (T(FH)) and T follicular regulatory (T(FR)) cells during Brucella infection. Inhibition of B cell and CD4(+) T cell interaction via CD40L blockade enhances resistance to Brucella in a B cell dependent manner concomitant with suppression of T(FH) and T(FR) differentiation. Conversely, PD-1 blockade increases Brucella burdens in a B and CD4(+) T cell dependent manner while augmenting T regulatory (T(Reg)) and T(FR) responses. Intriguingly, T(FR) deficiency enhances resistance to Brucella via a B cell dependent, but antibody independent mechanism. Collectively, these results demonstrate B cells support T(FR) responses that promote susceptibility to Brucella infection independent of the antibody response.