The heat-stable antigen determines pathogenicity of self-reactive T cells in experimental autoimmune encephalomyelitis

Induction of myelin-specific CD4 T cells is a pivotal event in the developm ent of experimental autoimmune encephalomyelitis (EAE). Other checkpoints i n EAE pathogenesis have not been clearly defined, although multiple genetic loci are known to influence EAE development. We report here that targeted mutation of the heat-stable antigen (HSA) abrogates development of EAE desp ite a complete lack of effect on induction of autoimmune T cells. To test w hether T-cell expression of HSA is sufficient, we created transgenic mice i n which HSA is expressed exclusively in the T-cell lineage. We found that t hese mice remain resistant to EAE induction. Adoptive transfer studies demo nstrate that both T cells and non-T cells must express HSA in order for the pathogenic T cells to execute their effector function. Moreover, HSAIg, a fusion protein consisting of the extracellular domain of the HSA and the Fc portion of immunoglobulin, drastically ameliorates the clinical sign of EA E even when administrated after self-reactive T cells had been expanded. Th us, identification of HSA as a novel checkpoint, even after activation and expansion of self-reactive T cells, provides a novel approach for immunothe rapy of autoimmune neurologic diseases, such as multiple sclerosis.