Identifying the cytokines provided by antigen presenting cells critical for generating an encephalitogenic T cell

Abstract Multiple sclerosis (MS) is a CD4 T cell-mediated demyelinating disease; however, what determines the encephalitogenicity of T cells remains unclear. Recognizing myelin peptides is not sufficient, as the frequencies of myelin-reactive T cells are similar between MS patients and healthy individuals. In experimental autoimmune encephalomyelitis (EAE), anti-CD3/CD28 antibodies-generated myelin-specific T cells do not transfer disease, but antigen-presenting cells (APC)-generated ones do. This suggests that the cytokines secreted by APC provide critical signals beyond T cell receptor activation and co-stimulation, contributing to an encephalitogenic phenotype. To identify the critical cytokines, myelin-specific T cells were activated with anti-CD3/CD28 in the presence of various cytokines, and the cells were adoptively transferred into naïve recipients. T cells generated with the combination of IL-6/IL-23 or IL-12/IL-23 induced severe EAE. We showed that IL-6 and IL-12 induced the initial expression of IL-23R on naïve T cells, and IL-23 further enhanced the expression of its own receptor. Neutralizing IL-6 or IL-12 in the APC-T cell culture significantly reduced the encephalitogenicity of T cells. Furthermore, IL-23R signaling induced STAT3 and STAT4 phosphorylation in both IL-6/IL-23 and IL-12/IL-23-generated T cells. Taken together, we have identified the minimal signals required to generate an encephalitogenic T cell, which provides potential targets for novel MS therapy.