title: CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection.
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.
authors: 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.
authors: David G
authors: DG
authors: Kugler
authors: Paul R
authors: PR
authors: Mittelstadt
authors: Jonathan D
authors: JD
authors: Ashwell
authors: Alan
authors: A
authors: Sher
authors: Dragana
authors: D
authors: Jankovic
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005938:Glucocorticoids / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid
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