INITIATION OF AUTOIMMUNE DIABETES IN NOD LT MICE IS MHC CLASS-I DEPENDENT/

MHC class II alleles clearly contribute a primary genetic component of susceptibility to autoimmune insulin-dependent diabetes mellitus (IDD M) in nonobese diabetic (NOD) mice. However, IDDM does not occur in NO D mice made MHC class I-deficient by a functionally inactivated beta(2 )-microglobulin allele (beta 2m(null)). In the present study the beta 2m(null) mutation was used to examine the relative contributions of MH C class I and class II-dependent T cell responses for initiating autoi mmune pancreatic beta cell destruction in NOD mice. Splenocytes from d iabetic NOD donors transferred IDDM to both lymphocyte-deficient NOD-s cid (class I+) and NOD-scid.beta 2m(null) mice (class I-). In contrast , splenocytes from young prediabetic NOD donors only transferred IDDM to class I+, but not class I- NOD-scid recipients. However, splenocyte s from prediabetic NOD donors did transfer IDDM to NOD-scid.beta 2m(nu ll) recipients previously engrafted with class I+, but not class I-, p ancreatic islets. CD4(+) T cell lines reactive against some syngeneic class I+ targets could be isolated from NOD.beta 2m(null) mice. Howeve r, NOD.beta 2m(null) T cells underwent activation-driven deletion when transferred into class I+ NOD-scid recipients. Hence, the class I aut oreactive T cells present in NOD.beta 2m(null) donors did not elicit I DDM when transferred into class I+ NOD-scid recipients. Collectively, these results show that autoimmune IDDM in NOD mice is initiated by MH C class I-dependent T cell responses, but this leads to the subsequent activation of additional T cell populations that can mediate pancreat ic beta cell destruction in a MHC class I-independent manner.