Human Tc17 cells harbor potent immune suppressive potential, whereas Tc1 cells lack suppressive ability

Abstract Regulatory T-cells keep untoward immune responses under control. In several autoimmune diseases, there is a substantial regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that acute relapses of Multiple Sclerosis are characterized by a deficit of CD8+ T-cell mediated immune-suppression. Similar to CD4+ T-cells, lineages for CD8+ cytotoxic T-cells (Tc) are predominantly determined by the cytokine milieu during differentiation. We hypothesized that distinct Tc lineages may harbor differential ability to suppress effector CD4+ T-cell responses. To test this hypothesis, we obtained purified human naïve CD8+ T-cells and activated them in different in-vitro conditions to differentiate them toward Tc0 (control), Tc1, Tc2 and Tc17 lineages. We then tested their ability to suppress various types of CD4+ T-cells in flow cytometric suppression assays. We observed that Tc0 controls and Tc2 cells had comparable suppression. However, Tc1 cells showed significant loss of suppressive ability. Interestingly, Tc17 cells exhibited significantly greater suppression of effector cells of various lineages (including bulk ex-vivo CD4+ T-cells as well as in-vitro differentiated Th1 and Th17 cells). Tc17 cells also showed the greatest proportion of CD8+ T-cells with a terminally differentiated phenotype (CD27−/CD45RO−), which we have previously shown to harbor the highest suppressive ability in a neuroantigen-specific setting. These studies illustrate that Tc17 cells, known to play a vital role in infection, tumor and autoimmunity, may have an important immune-regulatory function against effector CD4+ T-cells that could be harnessed in the design of CD8+ T-cell based immune-modulatory therapy.