Immunosuppressive roles for IL-10 and IL-4 in human infection. In vitro modulation of T cell responses in leprosy.
IL-10 and IL-4 have been shown to exert an inhibitory effect on cell-mediated immune responses. Our previous studies of leprosy demonstrated that IL-10 and IL-4 mRNA were preferentially expressed in lesions from lepromatous patients, those immunologically unresponsive individuals that manifest widespread infection. To define more precisely the regulatory roles of these two cytokines in the immune response to infection, we studied in vitro responses to Mycobacterium leprae. M. leprae triggered IL-10 release from PBMC of patients and healthy donors; the predominant source of the IL-10 was found to be monocytes/macrophages. Stimulation of PBMC in the presence of neutralizing anti-IL-10 mAb indicated that endogenous IL-10 production inhibits PBMC proliferation and release of TNF-alpha, GM-CSF, and IFN-gamma. Paradoxically, studies using neutralizing anti-IL-4 mAb indicated that endogenous IL-4 production enhances PBMC proliferative responses most strikingly in lepromatous patients. We found that rIL-4 expanded CD8+ T cells from lepromatous patients in vitro. CD8+ T cells from lepromatous patients have been shown to suppress CD4+ T cell responses, in part by the release of IL-4. Our study indicated that endogenous IL-4 production inhibited IL-10 secretion and, concomitantly, increased TNF-alpha and GM-CSF release. The present data suggest that, on balance, IL-4 and IL-10 contribute to immunosuppression in human infectious disease.
Division of Dermatology, University of California, Los Angeles School of Medicine 90024-1750.
P A
PA
Sieling
J S
JS
Abrams
M
M
Yamamura
P
P
Salgame
B R
BR
Bloom
T H
TH
Rea
R L
RL
Modlin
D002460:Cell Line; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D007918:Leprosy / Q000276:immunology* / Q000378:metabolism; D015440:Leprosy, Lepromatous / Q000276:immunology; D015441:Leprosy, Tuberculoid / Q000276:immunology; D008213:Lymphocyte Activation; D009166:Mycobacterium leprae / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor