A Novel Role for TGF-β and IL-10 in the Induction of Immune Privilege

Abstract

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-β, 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-β 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-β and anti-IL-10 Ab lost their ability to induce ACAID. In the absence of TGF-β, 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-β. Thus, TGF-β 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.

Overexpression and Interactions of Interleukin‐10, Transforming Growth Factor β, and Vascular Endothelial Growth Factor in Esophageal Squamous Cell Carcinoma

“…Normally, in the immune-privileged organs of the body (e.g., eye, testes), TGF-b is expressed and induces IL-10 by an obscure mechanism. Alteration of APC cytokines leads to immune privilege in these sites [37]. There may be similar interactions in tumors that enhance immune privilege, and concomitant expression of IL-10 and TGF-b could be responsible for it.…”

Anti‐CD30‐IL‐12 antibody‐cytokine fusion protein that induces IFN‐γ secretion of T cells and NK cell‐mediated lysis of Hodgkin's lymphoma‐derived tumor cells

“…IL‐12 is an extremely pleiotropic cytokine and plays a key role in linking innate cellular immunity to an adaptive Th1 response against pathogens and tumor cells1 by counteracting a Th2 immune response 2. IL‐12 production by antigen presenting cells and its function on immune cells, however, is negatively regulated by the Th2 cytokines IL‐10 and TGF‐β 3, 4. These cytokines are also present in lesions with Hodgkin's disease5 suggesting that they are involved in immunosuppression observed frequently in those patients.…”

“…2 IL-12 production by antigen presenting cells and its function on immune cells, however, is negatively regulated by the Th2 cytokines IL-10 and TGF-␤. 3,4 These cytokines are also present in lesions with Hodgkin's disease 5 suggesting that they are involved in immunosuppression observed frequently in those patients.…”