Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria

Abstract

CD4 T cell-dependent antibody responses are essential for limiting Plasmodium parasite replication and the severity of malaria; however, the factors that regulate humoral immunity during highly inflammatory, Th1-biased systemic infections are poorly understood. Using genetic and biochemical approaches, we show that Plasmodium infection-induced type I interferons limit T follicular helper accumulation and constrain anti-malarial humoral immunity. Mechanistically we show that CD4 T cell-intrinsic type I interferon signaling induces T-bet and Blimp-1 expression, thereby promoting T regulatory 1 responses. We further show that the secreted effector cytokines of T regulatory 1 cells, IL-10 and IFN-γ, collaborate to restrict T follicular helper accumulation, limit parasite-specific antibody responses, and diminish parasite control. This circuit of interferon-mediated Blimp-1 induction is also operational during chronic virus infection and can occur independently of IL-2 signaling. Thus, type I interferon-mediated induction of Blimp-1 and subsequent expansion of T regulatory 1 cells represent generalizable features of systemic, inflammatory Th1-biased viral and parasitic infections that are associated with suppression of humoral immunity.

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…During P. chabaudi infection, IFNAR -/-mice had elevated (72), unchanged (21), or reduced parasitemia (73,74). The role of type I IFN in the control of P. yoelii (another model of nonlethal blood-stage malaria) is also variable, as disruption of type I IFN signals has been demonstrated to either increase (75) or decrease parasite burden (28,33). Furthermore, increased type I IFN signals associated with knockout of the IRF3 repressor FOSL1 lead to reduced parasite burden (76).…”

Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis

“…These would be interesting targets to explore in this system as well. Indeed, extended expression of type I IFN or IFN-␥ has recently been shown to inhibit germinal center production in chronic P. berghei and P. yoelii infections (40,41).…”

“…Actually, CD4 T cell exhaustion has not been well documented in any situation. Instead, there is a concerted change in the cytokine profile of chronically stimulated T cells in LCMV and malaria away from Th1 or Tfh commitment (40,41,(47)(48)(49), suggesting that the effect of chronic infection on CD4 T cells is different than that on CD8 cells. On the other hand, PD-1 is expressed on human T cells in P. falciparum infections (44), and T cell proliferation is reduced in areas of continuous exposure to P. falciparum compared to those with successful control programs (21).…”

Immunological mechanisms controlling blood-stage parasites in mouse models of malaria

“…During the preparation of this report, four other studies complemented the current findings [345][346][347][348]. Among these, Zander and colleagues demonstrated that IFN-I limited accumulation of Tfh cells, thereby impairing humoral immune responses in Py17XNL-infected mice [346].…”

“…Among these, Zander and colleagues demonstrated that IFN-I limited accumulation of Tfh cells, thereby impairing humoral immune responses in Py17XNL-infected mice [346]. Mechanistically, these defects associated with IFN-I induced Tr1 formation and the production of both IL-10 and IFNg, via Blimp1 and T-bet signalling.…”