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C.M. Watte, T. Nakamura, J. Ortaldo, J. Stein Streilein; Ly49 C/I is a Co–Signaling Molecule Required for the Induction of ACAID . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2918.
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Ly49 C/I is a member of a family of inhibitory molecules that are expressed by NK, NKT and a minor population of T cells that when ligated down–regulate inflammatory cytokine production. The purpose of this study was to examine the function of Ly49 C/I in the development of peripheral tolerance induced through the eye (ACAID).
In–vivo: Following ACAID induction, peripheral tolerance, was assessed by measuring suppression of delayed hypersensitivity (DH) responses in mice. To determine the role of Ly49C/I, mice were treated with anti–Ly49 C/I blocking mAbs, IF8, 5E6 F(ab’)2 or control antibody 4D11, prior to ACAID induction. To determine the requirement of Ly49C/I+ iNKT cells in ACAID, iNKT cell deficient mice were reconstituted with enriched T cells or T cells depleted of Ly49C/I+ cells. In–vitro: To test the function of Ly49C/I, IL–10 mRNA expression levels were assessed by RT–PCR in iNKT cells following in vitro ACAID culture (co–culture of TGFß2 treated, antigen pulsed PEC and naïve splenocytes) with or without 5E6 F(ab’)2 and following co–stimulation with Ly49 C/I and TCR/CD3 complex by platebound 5E6 and 2C11 mAbs.
Eye induced peripheral tolerance was prevented by i.p. inoculation of either IF8 or 5E6 F(ab’)2 mAbs specific for Ly49 C/I (but not 4D11 mAb to the unrelated Ly49G2). Addition of 5E6 F(ab’)2 to in vitro ACAID cultures reduced the expression of IL–10 mRNA in iNKT cells. Crosslinking of Ly49 C/I and TCR/CD3 complex induced IL–10 mRNA expression in iNKT cells.
The expression of Ly49C/I by iNKT cells is required for the development of ACAID. Here, we show that Ly49 C/I functions as a co–stimulatory molecule for the production of IL–10 by iNKT during peripheral tolerance induction. IL–10 is an inducer of TGFß and inhibitor of IL–12 production and contributes to the immunosuppressive milieu during tolerance induction. Thus, the inhibitory molecule Ly49C/I, may also inhibit by promoting the production of immunosuppressive cytokines.
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