ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS

The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P . chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos -/- mice after drug-clearance. Following drug-clearance Icos -/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos -/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P . c . chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (T CM ) cells from wild-type and Icos -/- mice into tcrb -/- mice to directly evaluate the ability of T CM cells to give rise to Tfh cells revealed that T CM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P . c . chabaudi AS infection. While T CM cells from Icos -/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P . c . chabaudi AS.