Experimental autoimmune orchitis (EAO), the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C ( Kif1c ) as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3 . Mechanistically, we showed that the resistant Kif1c D2 allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L 578 →P 578 and S 1027 →P 1027 polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases. Author Summary Although the etiology of autoimmunity is not well known, a variety of studies have demonstrated that genetic predisposition is a major contributor to disease susceptibility and resistance. The major histocompatibility complex (MHC) is the primary genetic determinant of autoimmune disease susceptibility with multiple additional interacting loci required. However, the identification and characterization of non–MHC genes has been problematic, since most autoimmune diseases are polygenic with the individual genes exhibiting only partial or minimal penetrance. We previously identified Orch3 (mouse chromosome 11) as the most important immune-suppressive locus controlling dominant resistance to autoimmune orchitis, the principal animal model of non-infectious testicular inflammatory/autoimmune disease. Here, using congenic mapping, we identified kinesin family member 1C ( Kif1c ) as a positional candidate for Orch3 . Furthermore, over-expression of the Kif1c resistant allele in susceptible mice rendered animals autoimmune orchitis resistant, demonstrating that Kif1c is Orch3 . We propose that Kif1c plays an immunoregulatory role by controlling the levels of MHC class II in antigen presenting cells and consequently impacting autoreactive orchitogenic T cell responses. These finding are particularly relevant since polymorphism in other kinesins such as KIF21B and KIF5A have been associated with susceptibility and resistance to human autoimmune disease.
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