Mesenchymal Stem Cells Differentially Modulate Effector CD8+ T Cell Subsets and Exacerbate Experimental Autoimmune Encephalomyelitis

Mesenchymal stem cells (MSC) have emerged as a promising candidate for inflammatory suppression and disease amelioration, especially of neuro-inflammatory diseases such as multiple sclerosis (MS). Auto-reactive CD41 and CD81 T cells acquire pathogenic IFN gamma-producing-(Type I) and IL-17A-producing-(Type 17) effector phenotypes in MS and its animal model experimental autoimmune encephalomyelitis (EAE). Although MSC have been extensively demonstrated to suppress pathogenic effector CD41 T cells and CD41 T cell-mediated EAE, surprisingly few studies have addressed their modulation of effector CD81 T cells represented in MS or their impact on CD81 T cell-mediated EAE. We find that MSC differentially modulate CD81 T cell development depending on effector T cell subtype. MSC drive activated low-IFN gamma producers toward an enhanced high-IFN gamma Tc1-like phenotype but strongly inhibit the production of IL-17A and Tc17 polarization in vitro. These observations are underscored by differential MSC modulation of T cell activation, proliferation, and signature transcription factor up-regulation. In addition, effector CD81 T cells co-cultured with MSC exhibited increased production of IL-2, a molecule known to enhance IFN gamma, yet suppress IL-17A, production. Based on these in vitro effects on CD81 T cells, we next evaluated their impact on the severity of EAE. To better evaluate CD81 T cells, we immunized mice with MOG(37-50), which is a CD8-targeted epitope. Our results revealed a worsening of disease, consistent with their in vitro stimulation of Tc1 cells. These findings highlight the emerging duality of MSC in immune modulation and provide implications for their future use in immune-related diseases.