ICOS expression is not required for memory T cell formation or maintenance, but does promote Tfh cell differentiation and the humoral response after secondary Plasmodium chabaudi chabaudi AS infection

Abstract

Abstract In addition to promoting follicular helper T (Tfh) cell development, ICOS is implicated in memory T cell formation. We have shown in the P. chabaudi rodent model of malaria that the absence of ICOS leads to a persistent non-resolving infection due to a defect in Tfh cell maturation that prevents the formation of a germinal center (GC) response. Here we show that memory T cell formation and maintenance is not impaired in the absence of ICOS. The presence of CXCR5-expressing central memory T (TCM) cells in Icos−/− mice suggests that they are capable of differentiating into Tfh cells and supporting the humoral response after challenge. However, the formation of Tfh cells was impaired in Icos−/− mice after challenge. Similar to the primary infection, drug-cleared Icos−/− mice displayed a relapsing parasitemia that occurred more frequently and with higher peaks compared to wild-type mice, which was associated with a diminished and delayed parasite-specific antibody response and the absence of GCs. Surprisingly, GCs that were present in the spleen of wild-type mice pre-challenge dispersed shortly after challenge, but were apparent again by day 35 post-challenge. Adoptive transfer of TCM cells from wild-type and Icos−/− mice into Tcrβ−/− mice to directly evaluate the ability of TCM cells to differentiate into Tfh cells revealed that CXCR5+ and CXCR5− TCM cells from wild-type mice could develop into Tfh cells in the presence or absence of memory B cells. However, TCM cells from Icos−/− mice were incapable of differentiating into Tfh cells, although they could support GC-independent Ab production. Thus, ICOS expression is not required for memory T cell formation, but is necessary for the differentiation of TCM cells into Tfh cells after challenge.