Cutting Edge: IL-10 Is Essential for the Generation of Germinal Center B Cell Responses and Anti-Plasmodium Humoral Immunity

Abstract

IL-10 is a pleiotropic cytokine expressed during malaria, a disease characterized by short-lived, parasite-specific antibody responses. The role of IL-10 in regulating B cell responses during malaria is not known. Here we report that IL-10 is essential for anti-Plasmodium humoral immunity. We identify that germinal center (GC) B cell reactions, isotype-switched antibody responses, parasite control, and host survival require B cell-intrinsic IL-10 signaling. IL-10 also indirectly supports humoral immunity by suppressing excessive IFN-γ, which induces T-bet expression in B cells. Genetic ablation of either IFN-γ signaling or T-bet expression in B cells substantially enhanced GC B cell responses and anti-Plasmodium antibody production. Together, our data show that B cell-intrinsic IL-10 enhances while B cell-intrinsic IFN-γ and T-bet suppress GC B cell responses and anti-Plasmodium humoral immunity. These data identify critical immunoregulatory circuits in B cells that may be targeted to promote long-lived humoral immunity and resistance to malaria.

γδ T cells modulate humoral immunity against Plasmodium berghei infection

“…5 Moreover, we recently reported that Vc1 + cd T cells up-regulated IFN-c production after PbXAT infection and that Vc1 + cd T cells were necessary for protective immunity against PbXAT infection. 31 In this paper, we found that levels of IL-10 in cd T cells were higher during infection. The M-CSF-producing Vd6.3 + cd T cells prevented parasitaemia recrudescence, and most Vd6.3 + cd T cells expressed TCR Vc1 + .…”

“…5 The expansion of cd T cells led to the repression of IFN-c production in cd T cells on day 14 p.i. Therefore, expression levels of cytokines including IFN-c, IL-4, IL-6, IL-10 and IL-21, which are related to the development of humoral immunity [28][29][30][31][32] in cd T cells, were estimated during PbXAT infection and compared with those in cd T cells from naive WT mice (Fig. 9 However, it remains to be determined whether the production of other cytokines in cd T cells is altered during PbXAT infection.…”

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

“…We and others have shown that excessive IFN-γ limits humoral immunity (Zander et al, 2015, Ryg-Cornejo et al, 2016). In line with a potential deleterious effect of Tfh-derived IFN-γ expression, we recently identified that B cell-intrinsic IFN-γ signaling limits Plasmodium -specific GC B cell reactions (Guthmiller et al, 2016). Despite these analyses of effector Tfh responses, our current experiments show that potent B cell helper activity can be recalled from Th1-like, CXCR3 + Ly6C + T-bet + memory CD4 T cells, which can express IFN-γ ex vivo .…”

“…Despite these analyses of effector Tfh responses, our current experiments show that potent B cell helper activity can be recalled from Th1-like, CXCR3 + Ly6C + T-bet + memory CD4 T cells, which can express IFN-γ ex vivo . However, whether Th1-like Tfh memory cells either express IFN-γ in vivo or whether IL-21 (Perez-Mazliah et al, 2015) or IL-10 (Guthmiller et al, 2016) counteract the activity of IFN-γ during recall responses remains unknown. Although IL-21 expression was undetectable in Tfh- and Th1-like memory CD4 T cells ex vivo (not shown), current work in our laboratory is focused on dissecting these functional parameters as well as the transcriptional networks regulating Plasmodium -specific effector and memory Tfh cell development in vivo .…”

Interleukin-10 from CD4 + follicular regulatory T cells promotes the germinal center response

“…IL-10 can also promote B cell proliferation, survival, and differentiation into antibody-secreting plasma cells (24–28), although it is not known if Tfr cell-derived IL-10 can modulate the GC response. We demonstrate herein that indeed it does during acute viral infection.…”