T‐bet modulates the antibody response and immune protection during murine malaria

Oakley, Miranda S.; Sahu, Bikash; Lotspeich-Cole, Leda; Majam, Victoria; Pham, Phuong; Banerjee, Aditi; Kozakai, Y.; Morris, Sheldon L.; Kumar, Sanjai

doi:10.1002/eji.201344437

Cited by 20 publications

(17 citation statements)

References 28 publications

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“…T-bet, the master transcriptional regulator of T helper 1 cells, can also be expressed by GC B cells and several reports highlight that T-bet promotes class-switching and plasma cell differentiation (20, 21). By contrast, Plasmodium infection of T-bet deficient ( Tbx21 −/− ) mice is associated with enhanced parasite control and larger GC-derived anti- Plasmodium antibody responses (22), supporting that T-bet limits GC responses and anti-malarial humoral immunity. To dissect if IL-10 regulates the transcription factor profile of GC B cells, we first evaluated Bcl-6 and T-bet expression in GC B cells recovered from Plasmodium -infected WT and Il10 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

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

Guthmiller

Graham

Zander

et al. 2017

The Journal of Immunology

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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.

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Section: Resultsmentioning

confidence: 99%

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

Guthmiller

Graham

Zander

et al. 2017

The Journal of Immunology

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“…Thus, we next examined whether α-OX40 treatment expanded one or more functionally distinct CD4 T cell subsets. We first focused on T-bet + Th1 cells, as this subset is widely linked to protection against blood stage Plasmodium infection (Amante and Good, 1997; De Souza et al, 1997; Langhorne et al, 1990; Oakley et al, 2014). We found the fraction of effector CD4 T cells expressing T-bet, the MFI of T-bet, and the total number of T-bet + parasite-specific CD4 T cells were significantly elevated in mice treated with α-OX40 mAb (Figs 3B,C).…”

Section: Resultsmentioning

confidence: 99%

PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity

Zander

Obeng-Adjei

Guthmiller

et al. 2015

Cell Host & Microbe

109

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Summary The differentiation and protective capacity of Plasmodium-specific T cells are regulated by both positive and negative signals during malaria, but the molecular and cellular details remain poorly defined. Here we show that malaria patients and Plasmodium-infected rodents exhibit atypical expression of the co-stimulatory receptor OX40 on CD4 T cells and that therapeutic enhancement of OX40 signaling enhances helper CD4 T cell activity, humoral immunity and parasite clearance in rodents. However, these beneficial effects of OX40 signaling are abrogated following coordinate blockade of PD-1 co-inhibitory pathways, which are also up-regulated during malaria and associated with elevated parasitemia. Co-administration of biologics blocking PD-1 and promoting OX40 signaling induces excessive interferon-gamma that directly limits helper T cell-mediated support of humoral immunity and decreases parasite control. Our results show that targeting OX40 can enhance Plasmodium control and that crosstalk between co-inhibitory and co-stimulatory pathways in pathogen-specific CD4 T cells can impact pathogen clearance.

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“…However, control of parasite replication is lost and mice succumb to hyper-parasitemia and anemia ( 41 ). In a different rodent model of erythrocytic-stage malaria, P. yoelii 17X(NL), although activation of T-bet was detected on CD4 + T-cells early in infection ( 42 ), the infection can still be controlled in T-bet-deficient mice ( 43 ).…”

Section: Cd4 + T-cell Subsets Activated By Erythromentioning

confidence: 99%

CD4 T-Cell Subsets in Malaria: TH1/TH2 Revisited

Pérez‐Mazliah¹,

Langhorne²

2015

Front. Immunol.

138

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CD4+ T-cells have been shown to play a central role in immune control of infection with Plasmodium parasites. At the erythrocytic stage of infection, IFN-γ production by CD4+ T-cells and CD4+ T-cell help for the B-cell response are required for control and elimination of infected red blood cells. CD4+ T-cells are also important for controlling Plasmodium pre-erythrocytic stages through the activation of parasite-specific CD8+ T-cells. However, excessive inflammatory responses triggered by the infection have been shown to drive pathology. Early classical experiments demonstrated a biphasic CD4+ T-cell response against erythrocytic stages in mice, in which T helper (Th)1 and antibody-helper CD4+ T-cells appear sequentially during a primary infection. While IFN-γ-producing Th1 cells do play a role in controlling acute infections, and they contribute to acute erythrocytic-stage pathology, it became apparent that a classical Th2 response producing IL-4 is not a critical feature of the CD4+ T-cell response during the chronic phase of infection. Rather, effective CD4+ T-cell help for B-cells, which can occur in the absence of IL-4, is required to control chronic parasitemia. IL-10, important to counterbalance inflammation and associated with protection from inflammatory-mediated severe malaria in both humans and experimental models, was originally considered be produced by CD4+ Th2 cells during infection. We review the interpretations of CD4+ T-cell responses during Plasmodium infection, proposed under the original Th1/Th2 paradigm, in light of more recent advances, including the identification of multifunctional T-cells such as Th1 cells co-expressing IFN-γ and IL-10, the identification of follicular helper T-cells (Tfh) as the predominant CD4+ T helper subset for B-cells, and the recognition of inherent plasticity in the fates of different CD4+ T-cells.

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T‐bet modulates the antibody response and immune protection during murine malaria

Abstract: CD4+ Keywords: IgG1 r Immunity r Plasmodium yoelii r T-bet Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 20 publications

References 28 publications

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

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

PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity

CD4 T-Cell Subsets in Malaria: TH1/TH2 Revisited

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