title: Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
abstract: Although interferon gamma (IFN-gamma) secretion is essential for control of most intracellular pathogens, host survival often also depends on the expression of interleukin 10 (IL-10), a cytokine known to counteract IFN-gamma effector functions. We analyzed the source of regulatory IL-10 in mice infected with the protozoan parasite Toxoplasma gondii. Unexpectedly, IFN-gamma-secreting T-bet(+)Foxp3(-) T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals. Further analysis revealed that the same IL-10(+)IFN-gamma(gamma) population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-gamma, IL-10 production could be stimulated in IL-10(-)IFN-gamma(+) cells by further activation in vitro. In addition, experiments with T. gondii-specific IL-10(+)IFN-gamma(+) CD4 clones revealed that although IFN-gamma expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4(+) T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.
authors.affiliation: Immunobiology Section and 2Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. DJankovic@niaid.nih.gov
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Marika C
authors.initials: MC
authors.lastname: Kullberg
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Romina S
authors.initials: RS
authors.lastname: Goldszmid
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Collazo
authors.forename: Mark
authors.initials: M
authors.lastname: Wilson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Masahito
authors.initials: M
authors.lastname: Kamanaka
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016207:Cytokines / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000378:metabolism*; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D016753:Interleukin-10; D007371:Interferon-gamma