Mechanisms of Peripheral Tolerance following Intracameral Inoculation Are Independent of IL-13 or STAT6

Abstract

The peripheral tolerance that is elicited by the anterior chamber-associated immune deviation (ACAID) protocol is characterized by impairment of Th1 responses such as delayed-type hypersensitivity. It has been proposed that suppression of Th1 responses is mediated by a deviation toward Th2 responses. Because NKT cells have a prominent role in ACAID and NKT cell-derived IL-13 is required in a tumor model of tolerance, we postulated that NKT cell-derived Th2 cytokines might have a role in ACAID. However, contrary to the tumor model, in this study we show that NKT cells from IL-13-deficient mice or IL-4/IL-13 double deficient mice were able to reconstitute the capability of Jα18-deficient mice (lacking invariant NKT) to develop peripheral tolerance postintracameral inoculation of Ag. Also, we were able to induce peripheral tolerance directly in IL-13-deficient, IL-4/IL-13-double deficient, and STAT6-deficient mice by inoculation of Ag into their eye. We conclude that neither IL-4 nor IL-13 cytokines are required for the generation of efferent CD8+ T regulatory cells during eye-induced peripheral tolerance. We propose that Ags inoculated into the anterior chamber of the eye induce the immunoresponse to deviate from producing immune T effector cells to producing efferent T regulatory cells, rather than deviating from Th1- to Th2-type effector cells.

CD4+CD25+Tregs express an increased LAG-3 and CTLA-4 in anterior chamber-associated immune deviation

“…+ suppressor cell in ACAID. It has been shown that ACAID is a phenomenon mediated or maintained by generating an active regulatory T cell population to suppress DTH [15]. Regulatory CD4 + T cells are one of the suppressive populations responsible for the development of ACAID [2].…”

Therapies Based on Principles of Ocular Immune Privilege

“…Instead, the splenic cells of these mice secreted only TGF-␤ when stimulated with OVA in vitro. Furthermore, mice deficient in IL-4/IL-13 and STAT6 genes that are critical for Th2 development readily acquired ACAID suppression after intracameral inoculation of antigens [52]. Finally, the ability of ACAID and ACAID-tolerogenic APCs to suppress Th2-mediated pathogenesis adds the additional evidence to put the notion that ACAID is similar to a Th2 response to rest.…”

“…More recently, it has been clearly shown that at least the development of the CD8ϩ efferent T reg cell is not dependent on a Th2 response [52]. Thus the question arose as to whether the efferent CD8ϩ T reg cell might suppress Th2 responses, as well as Th1.…”

α-Galactosylceramide ameliorates autoimmune diabetes in non-obese diabetic mice through a suppressive effect mediated by CD8+ T cells

“…CD8 + Treg cells also perform their suppressive effect controlling a variety of immune responses, such as intestinal immunity, autoimmunity, oral tolerance, and in prevention of graft versus-host disease [29,30]. Interestingly, ACAID can be induced in IL-4, IL-13, or STAT6 knockout mice [31], indicating that Th2 and related cytokines are independent of CD8 + Treg-mediated immune suppression. Therefore, we propose that ␣GalCer mediates a similar mechanism in preventing T1D in NOD mice, since the suppression effect is also independent of STAT6 [23].…”