Regulation and role of GM-CSF production by human T helper cells in health and inflammation

点击翻译按钮获取中文摘要

T helper cells represent a growing family of specialized immune cell subsets that differ in their cytokine profile, migration properties and antigen targets. Th17 cells joined this family as a T helper cell lineage with major pathogenic functions in autoimmunity a few years ago. We have recently demonstrated the existence of two types of human Th17 cells with pro- and anti-inflammatory cytokine profiles. Anti-inflammatory Th17 cells co-produced IL-10 whereas pro-inflammatory Th17 cells co-produced IFN-gamma. They not only differed in function but also in priming requirements and pathogen specificities. These findings have revealed unexpected heterogeneity within the Th17 cell subset with implications for their role in health and disease.GM-CSF has recently been identified as a crucial pathogenic cytokine of the Th17 cell lineage for autoimmunity in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. It has even been shown to be more relevant for EAE pathogenesis than IL-17, which has so far been considered the Th17 signature cytokine. This suggests Th17 cell derived GM-CSF to be a promising therapeutic target in settings of inflammation. However, its expression, regulation and role in human T helper cells in health and disease have not been studied. Considering its pathogenic role in mice, a detailed characterization of GM-CSF regulation in human T cells will be important to provide a scientific basis for therapeutic targeting strategies. We therefore aim to identify and characterize GM-CSF producing T helper cells in humans. Our preliminary data demonstrate that GM-CSF can be expressed in T helper cells independently of IL-17 and also of any other lineage defining cytokine such as IFN-gamma, IL-4. This suggests the existence of GM-CSF-only producing T helper cells. We will study the requirements for their generation, their stability and plasticity, their migration properties as well as the transcriptional regulation of GM-CSF production in human T helper cells. We will also analyze whether the TCR repertoire of GM-CSF producing T helper cells differs from that of Th1, Th2 and Th17 cell subsets by using a novel method that allows the large-scale interrogation of the human TCR repertoire by using libraries of amplified T cells. This approach is based on the proliferation of antigen specific T helper cells in response to pathogen derived antigens and autoantigens. These studies will for the first time provide a characterization of human GM-CSF producing T helper cells and will determine whether a specialized GM-CSF producing subset with unique functions and phenotypic properties that differs from the classical T helper subsets exists. The proposed project will provide a scientific basis for therapeutic targeting of this cytokine in infections and autoimmune diseases.