B cells regulate the inflammatory CD4+ T cell response in Trypanosoma cruzi infection.

GOROSITO SERRÁN M; TOSELLO BOARI J; RAMELLO MC; BECCARIA CG; FIOCCA VERNENGO F; BERMEJO DA; AMEZCUA VESELY MC; MONTES CL; ACOSTA RODRIGUEZ EV; GRUPPI A

Congreso; LVII Reunión Anual de la Sociedad Argentina de Inmunología; 2014

B cell-deficient mice (mMT) infected with T. cruzi are able to control parasitemia similar to C57BL/6 wild type (WT) mice but present increased parasitemia by 10 days post-infection (dpi) and accelerated mortality. mMT and WT mice have similar tissue parasite load as determined by RT-PCR, indicating that mortality is not caused by uncontrolled parasitism. To assess possible causes of the increased susceptibility of mMT mice, we analyzed cytokine production and CD4+T cell responses in mMT and WT mice infected i.p. with 10000 trypomastigotes Y-br strain. Groups of 4-7 mice were sacrificed by 4, 9, 15, 20 dpi and sera and splenocytes were obtained. By 9 dpi, amounts of serum IFNg were increased in both infected mice strains, but were higher in mMT mice (p<0.01). Serum TNF amounts were increased in both mice strains by 9 dpi and afterwards diminished in WT and increased in mMT mice (15 and 21 dpi, p<0.001). CD4+T cells where the main IFNg producing population by 9 dpi and were higher in mMT mice in comparison to WT (p=0.0013). CD4+T cells were also the main TNF producers by 15 and 20 dpi and in mMT mice preferentially had a proinflammatory phenotype (CD4+Ly6C+). IL-10-producing cells were reduced in infected mMT mice due to not only the absence of IL-10+B cells present in WT mice, but also a decrease in the numbers of IL10-producing CD4+T cells (15 dpi, p<0.001). In vitro co-culture experiments showed that B cells controlled TNF production in splenocytes from infected mice incubated with T. cruzi antigens. TNF neutralization by mAbs prevented the cachexia observed in infected mMT mice but accelerated even more their mortality due to an exacerbated Th1 response with high amounts of IL12, IFNg, TNF. In these mice, CD4+Ly6C+ cells were increased in spleen at 30 dpi. Our data suggests that B-cell absence in T. cruzi infection could cause an altered activation of the CD4+T-cells, leading to a systemic imbalance in the host and mortality.