Plasmablasts constitute an early control of Trypanosoma cruzi replication and may regulate inflammation and immunopathology during the infection.

GOROSITO SERRÁN M; FIOCCA VERNENGO F; BECCARIA CG; CAPPELLO J; CAI Y; COCKBURN I; WAGLE M; PARISH I; PONGTORNPIPAT P; ZUÑIGA EI; MONTES CL; ACOSTA RODRIGUEZ EV; GARCIA VINUESA C; GRUPPI A

Congreso; Reunión Conjunta de Sociedades de Biociencias.; 2017

B cells are the only cells that differentiate into antibody-secretingcells (plasmablasts, PB; and plasma cells) and they can also shapeand regulate T cell responses through cytokine production. We havefound that PB generated in Trypanosoma cruzi infection have a highsurface expression of the inhibitory molecule PD-L1 and that thesecells were also present in other infections such as LCMV (Clone13) infection and Malaria. Since the PD1/PDL1 pathway is involvedwith disease in these chronic infections, we studied the biology ofPD-L1+PB generation and function. We have found that PD-L1+PBwere not driven by cytokines such as type I IFN, IFNg, IL-6 andTNF or by TLR2 and TLR4, because PD-L1+PB were present in T.cruzi infected mice deficient in all the cytokines and TLR mentioned.In fact, PD-L1+PB were driven by an antigen specific mechanism,since MD4 mice, whose B cells are specific for Hel, did not generatePB after T. cruzi infection. Additionally, PB generation required Tfhcollaboration since infected Bcl6f/fCD4Cre-pos mice presented adecrease in PB compared to Bcl6f/fCD4Cre-neg mice.Blimp1f/fCD23cre-pos mice infected with T. cruzi presented a significantincrease in parasitemia at day 9 post-infection(pi) (p<0.0001)but despite PB-absence these mice controlled parasitemia, showinga reduction of trypomastigotes in blood at day 12pi. Infected PB-deficientmice also presented a significant increase in PD1+CD4+Tcells, particularly those IFNg+TNF+ at day 18pi (p<0.001), indicatingthat CD4+T cells were disregulated in absence of PB. Furthermore,livers of infected PB-deficient mice presented more lesions relatedto inflammation. In vitro, co-culture of cell-sorted PD-L1+PB withCD4+ and CD8+T cells showed that PB suppressed cytokine productionby T cells in a PD-1/PD-L1 mechanism.In conclusion, PB are key players during T. cruzi infection becausethey constitute an early control of parasite replication and may regulateinflammation and immunopathology.