Abstract
Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/Du) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/Du and a susceptible allele of the Ubd promoter, we demonstrate that germline knockout of Tcrb-V13S1A1, which encodes the Vβ13a T cell receptor β chain, completely prevents diabetes. Using the RT1B/Du-identical LEW.1W rat, which does not develop T1D despite also having the same Tcrb-V13S1A1 β chain gene but a different allele at the Ubd locus, we show that knockout of the Ubash3a regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the Vβ13a TCR and its class II RT1u ligand suggests a mechanism by which a germline TCR β chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the Vβ13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity.
Highlights
As with human type 1 diabetes (T1D), autoimmune diabetes occurs in various rat strains with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1.B/Du ) [1,2]
We modeled the Vβ13a TCR and its recognition of insulin B:9-23 peptide bound to the rat class II MHC molecule, RT1Bu, using previously described algorithms that predict structures of TCRs [19] and TCR-pMHC complexes [20]
These observations strongly suggest, but do not prove, that the TCR encoded by the susceptible allele of Tcrbv13, Vβ13a, is critical at the very beginning of the diabetogenic process, probably in the thymus, when it encounters autoantigenic peptide in the context of RT1B/Du MHC
Summary
As with human type 1 diabetes (T1D), autoimmune diabetes occurs in various rat strains with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1.B/Du ) [1,2]. Among such rats, T1D is spontaneous in BBDP [3], Komeda [4] and LEW.1AR1 [5] rats, and it can be induced by immunological perturbation in LEW.1WR1 rats. More than 50 other loci, largely associated with immunoregulation, have been genetically mapped in humans and animals with T1D [6,7]. A permissive allele for this gene, Tcrb-V13S1A1, which encodes Vβ13a, is expressed in six diabetes-susceptible, RT1.B/Du rat strains (including LEW.1WR1), whereas three diabetes-resistant RT1.B/Du strains express either Tcrb-V13S1A2, which encodes Vβ13b (e.g., WF rats), or carry the pseudo-gene Tcrb-V13S1A3P (F344 rats) [13,14]
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