Abstract
Early plasmablast induction is a hallmark of Plasmodium infection and is thought to contribute to the control of acute parasite burden. Although long understood to be a T-cell dependent phenomenon, regulation of early plasmablast differentiation, however, is poorly understood. Here, we identify a population of CD4+ T cells that express the innate NK cell marker NK1.1 as an important source of T cell help 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 generation is independent of CD1d but critically reliant on MHC-II. CD4+ T cells that express NK1.1 early after activation produce IFN-γ and IL-21, and express the follicular helper T (Tfh) cell markers ICOS, PD-1 and CXCR5 more frequently than NK1.1− CD4+ T cells. Further analysis of this population revealed that NK1.1+ Tfh-like cells were more regularly complexed with plasmablasts than NK1.1− Tfh-like cells. Ultimately, depletion of NK1.1+ cells impaired class-switched parasite-specific antibody production during early Plasmodium yoelii infection. Together, these data suggest that expression of NK1.1 defines a population of rapidly expanding effector CD4+ T cells that specifically promote plasmablast induction during Plasmodium infection and represent a subset of T cells whose modulation could promote effective vaccine design.
Highlights
Despite decades of research, a highly efficacious vaccine against the protozoan parasite Plasmodium has yet to be developed, and malaria continues to remain a significant global health problem [1]
A TCR-βhiNK1.1+ population of CD4+ T cells emerged in the spleen as early as day 5 post infection (p.i.) (Figure 1A), and this population phenotypically resembled NK1.1-expressing T cells previously described in the spleen following infection with P. yoelii sporozoites [10]
NK1.1 expression was not limited to CD4+ T cells, as splenic CD8+ T cells upregulated this marker after P. yoelii infection (Supplemental Figures 1B,C)
Summary
A highly efficacious vaccine against the protozoan parasite Plasmodium has yet to be developed, and malaria continues to remain a significant global health problem [1]. Resistance from severe disease is mediated in part by parasite-specific Abs, protective anti-Plasmodium Abs are slow to develop in humans and challenging to induce artificially [2]. Vaccine failure has been attributed to antigenic variation and genetic polymorphisms within the P. falciparum (the predominant disease-causing parasite of humans) genome as a whole, as well the parasite’s ability to modulate expression of essential parasite proteins such as PfEMP-1 [3]. NK1.1-Expressing CD4+ T Cells factors, as well as others employed by the parasite, lend credence to the idea that P. falciparum subverts B cell responses in a manner that results in the inefficient acquisition of protective Abs [2]. Further insight into how Plasmodium infection shapes the subsequent immune response, including its impact on T and B cell differentiation, could lead to novel vaccine strategies designed to stimulate the production of high affinity, parasite-specific Abs
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