Article

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis during Plasmodium berghei ANKA Murine Malaria.

Division of Bacterial, Parasitic, and Allergenic Products, U.S. Food and Drug Administration, Rockville, MD 20852.
The Journal of Immunology (Impact Factor: 5.36). 09/2013; DOI: 10.4049/jimmunol.1300396
Source: PubMed

ABSTRACT The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4(+) T cells. However, the role of the Th1 CD4(+) T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet-deficient (Tbx21(-/-)) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 ± 3.1% versus 10.9 ± 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21(-/-) mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21(-/-) mice was associated with diminished numbers of IFN-γ-producing CD4(+) T cells in the spleen and a lower accumulation of CD4(+) and CD8(+) T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3(+) CD4(+) T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival.

0 Bookmarks
 · 
46 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Frontiers in Immunology 01/2014; 5:671.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor T-bet has been most prominently linked to NK and T cell production of IFN-γ, a cytokine required for the control of a diverse array of intracellular pathogens. Indeed, in mice challenged with the parasite Toxoplasma gondii, NK and T cell responses are characterized by marked increases of T-bet expression. Unexpectedly, T-bet(-/-) mice infected with T. gondii develop a strong NK cell IFN-γ response that controls parasite replication at the challenge site, but display high parasite burdens at secondary sites colonized by T. gondii and succumb to infection. The loss of T-bet had a modest effect on T cell production of IFN-γ but did not impact on the generation of parasite-specific T cells. However, the absence of T-bet resulted in lower T cell expression of CD11a, Ly6C, KLRG-1, and CXCR3 and fewer parasite-specific T cells at secondary sites of infection, associated with a defect in parasite control at these sites. Together, these data highlight T-bet-independent pathways to IFN-γ production and reveal a novel role for this transcription factor in coordinating the T cell responses necessary to control this infection in peripheral tissues. Copyright © 2015 by The American Association of Immunologists, Inc.
    Journal of immunology (Baltimore, Md. : 1950). 01/2015;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both upregulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L upregulation on DCs, and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells toward type 2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type 2 polarization may represent a key immune regulatory mechanism for protection against a broad array of disorders, such as inflammatory, infectious, and autoimmune diseases, which can be hijacked by tumors to evade immunity. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; · 7.21 Impact Factor