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J Exp Med. 2013 Sep 23;210(10):1919-27. doi: 10.1084/jem.20122300. Epub 2013 Aug 26.

CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection.

Author information

1
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases; 2 Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute; and 3 The Johns Hopkins University/National Institutes of Health Graduate Partnership Program; National Institutes of Health, Bethesda, MD 20892.

Abstract

Synthetic glucocorticoids (GCs) are commonly used in the treatment of inflammatory diseases, but the role of endogenous GCs in the regulation of host-protective immune responses is poorly understood. Here we show that GCs are induced during acute Toxoplasma gondii infection and directly control the T cell response to the parasite. When infected with toxoplasma, mice that selectively lack GC receptor (GR) expression in T cells (GR(lck-Cre)) rapidly succumb to infection despite displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate cytokines IL-12 and IL-27. Mortality in the GR(lck-Cre) mice was associated with immunopathology and hyperactive Th1 cell function as revealed by enhanced IFN-γ and TNF production in vivo. Unexpectedly, these CD4(+) T lymphocytes also overexpressed IL-10. Importantly, CD4(+) T cell depletion in wild-type or GR(lck-Cre) mice led to ablation of the GC response to infection. Moreover, in toxoplasma-infected RAG(-/-) animals, adoptive transfer of CD4(+) T lymphocytes was required for GC induction. These findings establish a novel IL-10-independent immunomodulatory circuit in which CD4(+) T cells trigger a GC response that in turn dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is critical for preventing collateral tissue damage and promoting host survival.

PMID:
23980098
PMCID:
PMC3782051
DOI:
10.1084/jem.20122300
[Indexed for MEDLINE]
Free PMC Article
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