A subset of NK1.1+ follicular helper CD4+ T cells promotes early extrafollicular plasmablast production during Plasmodium yoelii infection

Abstract

Abstract Early plasmablast induction is a hallmark of Plasmodium infection, including P. yoelii, and is thought to be essential for control of acute parasite burden. Although long understood to be a T-cell dependent phenomenon, control of early plasmablast differentiation in response to Plasmodium is poorly understood. Here, we identify a subset of CD4+ T cells that express the innate NK cell marker NK1.1 as being critical for early plasmablast and parasite-specific Ab production. Interestingly, NK1.1+ CD4+ T cells arise from conventional, naive NK1.1− CD4+ T cells and their induction is independent of CD1d but critically reliant on MHC-II. Early NK1.1+ CD4+ T cells express more ICOS than conventional (NK1.1−) CD4+ T cells and subsequently expand more rapidly and give rise to PD-1high follicular helper T (Tfh) cells more frequently than conventional CD4+ T cells. Further study of this population revealed that NK1.1+ Tfh cells are more likely to be complexed with plasmablasts than conventional Tfh cells. Moreover, NK1.1+ Tfh cells interact almost exclusively with PD-L1high plasmablasts and more readily express markers indicative of apoptosis than conventional Tfh cells. Ultimately, depletion of NK1.1+ cells significantly impairs class-switched parasite-specific antibody production during early P. yoelii infection. Together, these data suggest NK1.1+ Tfh cells are essential for driving early plasmablast induction during Plasmodium infection and may represent a unique Tfh cell subset whose modulation could promote effective vaccine design.