1. Interactions between B cells and T follicular regulatory cells enhance susceptibility to Brucella infection independent of the anti-Brucella humoral response.
- Author
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Dadelahi, Alexis S., Abushahba, Mostafa F. N., Ponzilacqua-Silva, Bárbara, Chambers, Catherine A., Moley, Charles R., Lacey, Carolyn A., Dent, Alexander L., and Skyberg, Jerod
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B cells , *REGULATORY T cells , *HUMORAL immunity , *BRUCELLA , *OVARIAN follicle , *B cell receptors , *T cells , *ANTIGEN presentation - Abstract
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 (TFH) and T follicular regulatory (TFR) 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 TFH and TFR differentiation. Conversely, PD-1 blockade increases Brucella burdens in a B and CD4+ T cell dependent manner while augmenting T regulatory (TReg) and TFR responses. Intriguingly, TFR deficiency enhances resistance to Brucella via a B cell dependent, but antibody independent mechanism. Collectively, these results demonstrate B cells support TFR responses that promote susceptibility to Brucella infection independent of the antibody response. Author summary: Brucella can cause a life-long infection in humans, mice and livestock making it an ideal organism for investigating the mechanisms that pathogens employ to subvert host immunity and cause chronic infection. Here, we determined how B cell effector functions enhance susceptibility to Brucella. We found that animals with B cells that are unable to recognize Brucella through their BCR are resistant to infection. We also found that B cells alter the function of CD4+ T cells during Brucella infection in a MHCII- and CD40:CD40L-dependent manner. Moreover, we show that B cells promote development of T follicular regulatory cells that in turn enhance susceptibility to Brucella in an antibody independent manner. This was of particular interest, because to our knowledge, an antibody independent function of T follicular regulatory cells in modulating susceptibility to infection has not been previously reported. Collectively, this study highlights mechanisms by which Brucella infection subverts B and CD4+ T cell interactions to promote host susceptibility to infection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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