ICOS expression is required for maintenance but not the formation of germinal centers in the spleen in response to P. yoelii infection.

Abstract

Inducible T cell co-stimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and thus germinal center (GC) formation. Previously, our lab showed in a Plasmodium chabaudi infection model that Icos-/- mice did not form GCs despite a persistent infection and thus a continued antigen (Ag) load. Here, we show that resolution of a primary infection with P. yoelii, was delayed in Icos-/- mice. This phenotype was associated with a reduction in the accumulation of Tfh-like and GC Tfh cells and an early deficiency in Ag-specific antibody (Ab) production. However, Icos-/- mice maintained their ability to form GCs, though they were less frequent in number than in wild-type (WT) mice. Furthermore, while Ab production in Icos-/- mice matched that of WT mice after the infection cleared, the Abs lacked signs of affinity maturation, suggesting functional defects associated with these GCs. Eventually, these GC structures dissipated more rapidly in Icos-/- mice than in WT mice. Moreover, the ability of Icos-/- mice to form these GC structures is not reliant on the high Ag load associated with P. yoelii infections, as GC formation was preserved in Icos-/- mice treated with early with atovaquone. Finally, mice were unable to form secondary GCs in the absence of ICOS after re-challenge. Overall, these data demonstrate the necessity of ICOS in the maintenance of Tfh cells, the formation and maintenance of sufficient numbers of functioning GCs, and the ability to generate new GC structures after re-infection with P. yoelii.