A novel role for TGF-beta and IL-10 in the induction of immune privilege.
Immune privilege within the eye is due in large part to Ag-specific, systemic down-regulation of Th1 immune responses, a phenomenon termed anterior chamber-associated immune deviation (ACAID). Since the cytokine milieu influences Th cell differentiation, we hypothesized that TGF-beta, an immunosuppressive cytokine secreted by ocular cells, determines the nature of the immune response to Ags introduced into the anterior chamber. Accordingly, an in vitro model of the eye was used to determine the cytokine profile of ocular APC. TGF-beta preferentially induced APC to secrete a Th2-type cytokine, IL-10, and concomitantly suppressed the production of the Th1-inducing cytokine, IL-12. APC incubated with TGF-beta and anti-IL-10 Ab lost their ability to induce ACAID. In the absence of TGF-beta, Ag-pulsed APC preferentially secreted IL-12 and elicited Ag-specific Th1 responses (i.e., delayed-type hypersensitivity (DTH)). However, APC pulsed with Ag and exogenous IL-10 behaved in a manner similar to ocular APC and induced Ag-specific suppression of DTH. The role of IL-10 in ACAID was confirmed in IL-10 knockout mice. Anterior chamber injection of OVA into IL-10 knockout mice elicited normal DTH responses rather than ACAID. Moreover, Ag-pulsed APC from IL-10 knockout mice were unable to induce ACAID following in vitro treatment with TGF-beta. Thus, TGF-beta predisposes ocular APC to secrete IL-10 during Ag processing. This, in turn, directs the immune response away from a Th1 pathway and toward a Th2-like response in which DTH is suppressed.
D'Orazio
T J
TJ
Graduate Program in Immunology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Niederkorn
J Y
JY
D000818:Animals; D000867:Anterior Chamber / Q000166:cytology / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016207:Cytokines; D016212:Transforming Growth Factor beta; D016753:Interleukin-10