Interleukin-17 (IL-17) producing CD4+ T helper cells (Th17) cells are linked to the pathogenesis of highly prevalent inflammatory diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). To further support the role of IL-17 and Th17 cells in MS, a recent small clinical trial with anti-IL-17 (AIN457, Secukinumab) conducted by Novartis, has shown beneficial clinical effects in reducing the lesion load and clinical disease in MS patients (5, 6). In addition to MS, Th17 cells were also found to be associated with other autoimmune and chronic inflammatory diseases such as RA, ankylosing spondylitis (AS), inflammatory bowl disease (IBD), and psoriasis (7, 8). Therefore, IL-17 and Th17 cells are not only critical for studies of MS but also in other human autoimmune diseases, as in vivo neutralization of IL-17 has also shown high degree of clinical efficacy in both psoriasis and AS (9, 10). Although IL-17 and IL-23-Receptor expressing Th17 cells have been genetically linked to IBD, administration of the same anti-IL-17 antibody (AIN457, Secukinumab) in IBD patients did not inhibit the disease but if anything appeared to worsen the disease (11). This raises the issue of whether all Th17 cells are pathogenic and thus “en-block” deletion of Th17 cells or complete neutralization of IL-17 may result in the loss of tissue-protective Th17 cells. Indeed, it is now appreciated that not all Th17 cells are pathogenic. Recent discoveries imply that two different subtypes of Th17 cells, one that induces autoimmunity (pathogenic) and one that does not (non-pathogenic), cause this observed dichotomy. Possible findings that allow specific targeting of pathogenic Th17 cells would have major translational and therapeutic implications.
To date, the expression and function of co-inhibitory receptors has been most extensively described in CD8+ T cells, where the accumulation and overexpression of these co-inhibitory receptors is known to promote T cell dysfunction and exhaustion. This exhausted cell state is usually characterized by diverse deficits in effector function and leads to an impaired ability to clear chronic viral infections and cancer (14). In contrast, the role of co-inhibitory receptors in CD4+ T cell immunology is not as comprehensively studied however, classic co-inhibitory receptors, such as such as CTLA4 and PD-1, and their respective ligands have already been implicated in regulating differentiation and function of CD4+ T helper subsets, including Th17 cells (15, 16). Data show that e.g. the PD-1 pathway considerably influences Th17 cells by promoting their differentiation, but limiting their response during the effector phase. This is in line with increasing reports of manifestations of autoimmune like diseases in patients who receive cancer immunotherapies that block co-inhibitory receptors like CTLA-4 and PD-1 (17). While this therapy is usually aimed to restore the impaired CD8+ T cell function and restore anti-tumor immunity, the checkpoint blockade - directly or indirectly - appears to initiate the activity of pro-inflammatory CD4+ T cells.
This research project offered the unique opportunity to explore completely newly identified co-inhibitory receptors. To discover their role in regulating Th17 pathology and tumor immunity, we chose two promising G-coupled receptors that could potentially serve as direct targets for medical therapy: GPR65 and CysLTR2. We aimed to analyze whether they not only inhibit pathogenic Th17 cells but also promote differentiation of non-pathogenic Th17 cells. Further, we wanted to examine whether changes to the pathogenic signature of Th17 cells induced by co-inhibitory receptors also translated into altered pathogenicity in vivo. It was also of high interest to us to test how the expression of these newly discovered co-inhibitory receptors synergizes with other co-inhibitory receptors and how they can influence tumor immunity.
