Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
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.
Jankovic
Dragana
D
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
Kullberg
Marika C
MC
Feng
Carl G
CG
Goldszmid
Romina S
RS
Collazo
Carmen M
CM
Wilson
Mark
M
Wynn
Thomas A
TA
Kamanaka
Masahito
M
Flavell
Richard A
RA
Sher
Alan
A
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*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D016753:Interleukin-10; D007371:Interferon-gamma