Karolinska Research Lectures at NOBEL FORUM
September 17, 16.30
Vijay K. Kuchroo
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Title: Single-cell genomics identifies novel regulators of metabolic andfunctional states of Th17 cells
Recently a subset of interleukin (IL)-17-producing T cells (TH17) distinct from TH1 or TH2 cells was described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast to the effector T cells, CD4+CD25+, Fox-P3+ regulatory T cells (T-regs) inhibit autoimmunity and protect against tissue inflammation. TGF- is a critical differentiation factor for the generation of T-regs and using Foxp3-GFP “knock-in” mice we have shown that IL-6, an acute phase protein induced during infection, inflammation and injury inhibits the generation of Foxp3+ T-reg cells and induces proinflammatory Th17 cells (Bettelli et al., 2006). Our data therefore suggests a reciprocal relationship in the generation of pathogenic (Th17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury. Accumulating data suggests that there are three distinct steps in Th17 differentiation: Induction, Amplification and Stabilization mediated by distinct cytokines and loss of any of the cytokines (TGF-b, IL-6, IL-21 or IL-23) in the pathway results in a defect in generation of Th17 (Korn et al., 2009). However not all Th17 cells are pathogenic and induce autoimmunity, IL-23 is a key cytokine that induces pathogenicity in Th17 cells (Lee et al., 2012). Using expression profiling at very high temporal resolution, novel computational algorithms and innovative nano-wire based “knock-down” approaches, we have developed a regulatory network that governs the development of Th17 cells. The Th17 transcriptional network consists of two self-enforcing but mutually antagonistic modules, which are essential for maintaining a balance between Th17 and other CD4 T cell subsets including Tregs (Yosef et al. 2013, Wu et al., 2013).
In addition to high-density temporal microarray analysis, we have performed single-cell RNA-seq of Th17 cells in order to characterize cellular heterogeneity, identify subpopulations, functional states and learn how gene expression variation affects Th17 effector functions. We have identified novel regulators of Th17 cells both in vivo and in vitro that do not affect Th17 differentiation but affect pathogenic vs. non-pathogenic functional states of Th17 cells.
Host: Marie Wahren, Karolinska Institutet
Contact: Tatiana Goriatcheva, Nobel Office, Nobel Forum,
tel. 524 87805, firstname.lastname@example.org