ICOS Expression Is Required for Maintenance but Not the Formation of Germinal Centers in the Spleen in Response to...

Inducible T cell costimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and, thus, germinal center (GC) formation. Previously, our laboratory showed in a Plasmodium chabaudi infection model that Icos mice were significantly impaired in their ability to form GCs despite persistent infection and, thus, a continued antigen (Ag) load. Here, we show that the resolution of primary infection with Plasmodium 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 could form GCs, although they were less frequent in number than in wild-type (WT) mice. Nonetheless, the Ag-specific Abs from Icos^-/- mice 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 loads associated with P. yoelii infections, as GC formation was preserved in Icos mice treated with atovaquone. Finally, mice were unable to form secondary GCs in the absence of ICOS after rechallenge. 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 reinfection with P. yoelii.