Recent Insights into CD4+ Th Cell Differentiation in Malaria

Abstract

CD4 Th cell differentiation is crucial for protecting against blood-stage parasites, the causative agents of malaria. It has been known for decades that more than one type of Th cell develops during this infection, with early models proposing a biphasic Th1/Th2 model of differentiation. Over the past decade, a large body of research, in particular, reports over the past 2-3 y, have revealed substantial complexity in the Th differentiation program during infection. In this article, we review how several studies employing mouse models of malaria, and recent human studies, have redefined the process of Th differentiation, with a particular focus on Th1 and T follicular helper (Tfh) cells. We review the molecular mechanisms that have been reported to modulate Th1/Tfh differentiation, and propose a model of Th1/Tfh differentiation that accommodates observations from all recent murine and human studies.

Immune effector mechanisms in malaria: An update focusing on human immunity

“…While functional heterogeneity exists among CD4+ T cells, P. falciparum-specific Th1 CD4+ T cell responses appear to be highly context-dependent. 88 Children who had more than two infections per year had higher frequencies of IL10/IFNγ bifunctional CD4+ T cells, in contrast to bi-and monofunctional IFNγ/TNFα CD4+ T cells responses found in adults and children who had fewer prior P. falciparum infections. 93,144 IL10 is thought to counteract immunopathology in malaria and not play a direct role in parasite clearance.…”

“…Therefore, appropriately mobilized down‐regulation of protective immune effector mechanisms is critical for human survival. While functional heterogeneity exists among CD4+ T cells, P. falciparum ‐specific Th1 CD4+ T cell responses appear to be highly context‐dependent . Children who had more than two infections per year had higher frequencies of IL10/IFNγ bifunctional CD4+ T cells, in contrast to bi‐ and mono‐functional IFNγ/TNFα CD4+ T cells responses found in adults and children who had fewer prior P. falciparum infections .…”

“…The complexity of human Tfh cells has been investigated within the context of malaria in only a few studies, to date . After an episode of acute, uncomplicated malaria in Malian children, the less functional CXCR3+PD1+ Tfh1 subset appears to be preferentially activated to produce IL21 and pro‐inflammatory cytokines .…”

“…[82][83][84] The complexity of human Tfh cells has been investigated within the context of malaria in only a few studies, to date. [85][86][87][88] After an episode of acute, uncomplicated malaria in Malian children, the less functional CXCR3+PD1+ Tfh1 subset appears to be preferentially activated to produce IL21 and pro-inflammatory cytokines. 86 Even though these children had CXCR3−PD1+ Tfh cells that were capable of promoting class switching and MBC differentiation into plasmablasts in vitro, neither of these Tfh subsets correlated with the breadth or magnitude of antimalarial IgG antibody responses measured in their plasma.…”

Effects of type I interferons in malaria

“…In contrast, CD4 + helper T‐cell responses are crucial for inducing cellular and humoral immunity during blood‐stage Plasmodium infection . In particular, as recently reviewed elsewhere by our group, IFN‐ γ ‐producing, T helper type 1 (Th1) cells, and high‐affinity antibody‐inducing T follicular helper (Tfh) cells play particularly important roles in controlling and resolving blood‐stage infections. In addition, certain types of regulatory CD4 + T cells, in particular Type 1 regulatory (Tr1) cells that express the canonical immune‐suppressive cytokine IL‐10, are required to mitigate the possible deleterious effects of T‐cell‐mediated inflammation …”