Modulation of T helper cell functions by stress-sensing receptor NKG2D

• Applicant: Marina Babic Cac, Ph.D.
• Subject Area: Immunology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397528096

While the role of cytokines in driving the differentiation of activated CD4+ T cells towards different helper lineages is well established, the direct effect of innate receptors recognizing danger/stress signals has only started to be clarified. NKG2D represents one of the best-described stress recognizing receptors in NK cell biology. Human NKG2D+ CD4+ T cells have been described in many autoimmune and infectious diseases. Administration of blocking anti-NKG2D antibodies in mouse models of autoimmunity resulted in milder disease phenotype. However, since this antibody targets many cell types, the role of NKG2D+ CD4+ T cells in the pathogenesis of chronic inflammatory diseases remains unclear. In our previous work we could show increased frequency of NKG2D+ CD4+ T cells in the ovalbumin-induced arthritis (OIA) in C57BL/6 mice, which were characterized by increased expression of proinflammatory cytokines. In addition, the anti-NKG2D treatment of animals ameliorated the disease. NKG2D expression was confined to the Th1 and Th17 cell lineages, and associated on the one hand with higher IL-10 in Th1 cells and on the other hand enhanced IL-17A/F production in Th17 cells. The impact of NKG2D-mediated cytokine modulation of CD4+ T cells on the pathogenesis of autoimmune diseases as well as the underlying molecular mechanisms remain to be elucidated. Here we propose ex vivo/in vitro experiments using extensive flow cytometry profiling and state-of-the-art transcriptome analysis combined with in vivo mouse models of autoimmune diseases (OIA and EAE) using mouse mutants with NKG2D-deficiency in (CD4+) T cells as well as CD4+ T cell transfer models. Our project will bring to further understanding the role of innate receptors, specifically NKG2D in the modulation of T cell functions during chronic inflammation and autoimmunity and further validate the potential of NKG2D as a therapeutic target.

• DFG Programme: Research Grants