Tissue specific control of CD4+ T cells via IL-10 signaling

• Applicant: Professor Dr. Samuel Huber
• Subject Area: Immunology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 310356505

IL-10 is an important anti-inflammatory cytokine that is produced by various types of immune cells. Accordingly deficiency in IL-10 correlates with the development of chronic inflammatory diseases. Thus, IL-10 can act on antigen presenting cells and inhibit their maturation, thereby controlling CD4+ T-cell responses indirectly. Furthermore we and others have recently reported that IL-10 can also act on T cells directly thereby controlling inflammation of the intestine: IL-10 can directly act on regulatory T cells (Foxp3+Treg) promoting their suppressive function thereby indirectly controlling TH17 cells. Additionally IL-10 can also directly interact with TH17 cells thereby controlling their phenotype and expansion. On the contrary, it was shown in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)) that IL-10 is also able to directly promote survival of memory CD4+ T cells and therefore to support neuronal inflammation. In line with these seemingly contradictory data our preliminary results suggest important difference of the effect of IL-10 on different T helper cell subsets between the CNS (central nervous system) and the intestine.Based on these findings, we hypothesize that IL-10 has dual effects on CD4+ T cells, which can be both direct and indirect depending on the specific T helper cell subtype as well as tissue specific factors. In order to test this hypothesis we will use mouse models of intestinal and neural inflammation. Furthermore, we will use reporter Knock In mouse models (Foxp3 mRFP x Il-10 eGFP x Il-17a FP635) and transgenic mice with impaired (Cd4-dnIL-10R) or complete abrogation of IL-10 signaling (conditional IL-10R alpha Knockout) in order to specifically analyze the role of IL-10 signaling in Foxp3+ Treg and TH17 cells. We aim to first analyze whether the IL-10/IL-10(R)eceptor axis is differentially regulated during the cause of neuronal and intestinal inflammation. In a second step, we will determine if IL-10 signaling plays a differential role in regulating TH17 cells and Foxp3+ Treg during the induction and effector phase of EAE. Additionally, we will elucidate the tissue-specific role of IL-10 in the control of T-cell responses in the central nervous system (CNS). To this end, we will i) investigate the role of IL-10 for the Foxp3+ Treg-mediated control of TH17 cells in the CNS, ii) test whether Foxp3+ Treg control their activity in the CNS via a positive feedback loop of IL-10 signaling and iii) identify candidate genes that are regulated by IL-10 specifically in Foxp3+Treg in the CNS. These investigations will lead to a better understanding of the regulation of inflammation by IL-10 and may build the basis for new tissue-specific therapies for the treatment of autoimmune and chronic inflammatory diseases of the CNS and intestine.

• DFG Programme: Research Grants