Pathogenic and Protective T Cells in Toxoplasmosis

Project Details

Description

A successful cellular immune response to Toxoplasma gondii and many other
intracellular pathogens involves a delicate balance between the actions of IL-12, a proinflammatory
innate cytokine triggered by the parasite and IL-10, a regulatory cytokine
produced by adaptive T cells to prevent immunopathology. The overall goal of this
proposal is to explore how IL-12 controls the generation and persistence of parasitereactive
CD8 effector and memory cells required for protective immunity and how IL-10
acts in a novel autocrine fashion to avert tissue damage. Using a new mouse model with
T-cell lineage specific interference in IL-10 signaling, we have obtained evidence that IL-
10 activation of a T-cell intrinsic anti-inflammatory response is required to prevent
morbidity and mortality during T. gondii infection. We will use this transgenic and other
knockout mouse models to elucidate the kinetics, regulation and functional consequences
of IL-10 responsiveness during the Th1 response to T. gondii and explore a novel
mechanism for how IL-10 cell-autonomously restrains Th1 cytokine responses. We have
recently described four subpopulations of CD8 cells induced by immunization with the
cps-vaccine strain of T. gondii and have published evidence that IL-12 is critically
required for the generation of effector CD8 T cells expressing IFNγ, granzyme B and
KLRG1. In collaboration with Dr. Hidde Ploegh s laboratory at MIT, we have identified
the first Kb-restricted CTL epitope from T. gondii and our collaborators have also
developed a cloned mouse line bearing monoclonal na ve CD8 T cells reactive to this Kbrestricted
T. gondii antigen. Using these new mouse and immunological reagents, we will
elucidate the cytokine requirements, lineage relationships and functional significance of
the heterogenous CD8 T cell subsets induced by T. gondii vaccination and infection. We
will critically assess the costs and benefits of IL-12 signaling on the immediate and recall
CD8 protective response to re-infection.
StatusFinished
Effective start/end date9/26/096/30/16

Funding

  • National Institutes of Health: $386,100.00
  • National Institutes of Health: $369,914.00
  • National Institutes of Health: $386,100.00
  • National Institutes of Health: $390,000.00
  • National Institutes of Health: $390,000.00
  • National Institutes of Health: $393,525.00

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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