Inducible Costimulator Expressing T Cells Promote Parasitic Growth During Blood Stage ANKA Infection.

The lethality of blood stage (PbA) infection is associated with the expression of T-bet and production of cytokine IFN-γ. Expression of inducible costimulator (ICOS) and its downstream signaling has been shown to play a critical role in the T-bet expression and IFN-γ production. Although earlier studies have examined the role of ICOS in the control of acute blood-stage infection of AS (a non-lethal model of malaria infection), its significance in the lethal blood-stage of PbA infection remains unclear. Thus, to address the seminal role of ICOS in lethal blood-stage of PbA infection, we treated PbA-infected mice with anti-ICOS antibody and observed that these mice survived longer than their infected counterparts with significantly lower parasitemia. Anti-ICOS treatment notably depleted ICOS expressing CD4 and CD8 T cells with a concurrent reduction in plasma IFN-γ, which strongly indicated that ICOS expressing T cells are major IFN-γ producers. Interestingly, we observed that while ICOS expressing CD4 and CD8 T cells produced IFN-γ, ICOSCD8 T cells were also found to be producers of IFN-γ. However, we report that ICOSCD8 T cells were higher producers of IFN-γ than ICOSCD8 T cells. Moreover, correlation of ICOS expression with IFN-γ production in ICOSIFN-γ T cell population (CD4 and CD8 T cells) suggested that ICOS and IFN-γ could positively regulate each other. Further, master transcription factor T-bet importantly involved in regulating IFN-γ production was also found to be expressed by ICOS expressing CD4 and CD8 T cells during PbA infection. As noted above with IFN-γ and ICOS, a positive correlation of expression of ICOS with the transcription factor T-bet suggested that both of them could regulate each other. Taken together, our results depicted the importance of ICOS expressing CD4 and CD8 T cells in malaria parasite growth and lethality through IFN-γ production and T-bet expression.