Abstract
Autoimmune diseases are characterized by regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that CD8+ T-cells associated with acute relapse of multiple sclerosis are significantly deficient in their immune suppressive ability. We hypothesized that distinct CD8+ cytotoxic T-cell (Tc) lineages, determined by cytokine milieu during naïve T-cell differentiation, may harbor differential ability to suppress effector CD4+ T-cells. We differentiated purified human naïve CD8+ T-cells in vitro toward Tc0 (media control), Tc1 and Tc17 lineages. Using in vitro flow cytometric suppression assays, we observed that Tc0 and Tc17 cells had similar suppressive ability. In contrast, Tc1 cells showed significant loss of suppressive ability against ex vivo CD4+ T-cells and in vitro-differentiated Th0, Th1 and Th17 cells. Of note, Tc1 cells were also suboptimal in suppressing CD4-induced acute xenogeneic graft versus host disease (xGVHD) in vivo. Tc subtypes derived under various cytokine combinations revealed that IL-12-containing conditions resulted in less suppressive cells exhibiting dysregulated cytotoxic degranulation. RNA sequencing transcriptome analyses indicated differential regulation of inflammatory genes and enrichment in GM-CSF-associated pathways. These studies provide insights into the role of T-cell differentiation in CD8 suppressive biology and may reveal therapeutically targetable pathways to reverse suppressive deficit during immune-mediated disease.
Highlights
As key regulators of the immune response, T-cells can serve both causative and protective roles during immune-mediated damage [1,2,3,4,5,6,7,8]
We hypothesized that differentiation of naïve CD8+ T-cells along these pathways would result in variable immune-suppressive potential. Using both in vitro assay systems as well as an in vivo xenogeneic graft versus host disease model, we discovered that CD8+ T-cells differentiated toward the Tc1 phenotype had significantly lower suppressive ability
Deficient CD8-mediated regulation may be associated with greater disease severity, such as relapses of multiple sclerosis [29, 30]
Summary
As key regulators of the immune response, T-cells can serve both causative and protective roles during immune-mediated damage [1,2,3,4,5,6,7,8]. Similar evidence has accumulated in the context of autoimmune diseases such as type 1 diabetes, colitis, SLE-like disease, Graves' disease, among others [21,22,23,24,25]. These regulatory CD8+ T-cells function, in part, through suppression of autoreactive CD4+ responses [9, 14, 26,27,28]. We have demonstrated that acute MS relapses are characterized by a substantial deficit in the suppressive
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