IL10 is a predominantly anti-inflammatory cytokine that is critical in setting immune response amplitude. Genetic variation in IL10 or IL10R expression or function is associated with susceptibility to autoimmune and inflammatory diseases. The efficacy of many immunomodulatory therapies is IL10 dependent. Nevertheless, pharmacotherapy with IL10 has shown little benefit in several diseases, and in some experimental settings overexpression or pharmacologic treatment with IL10 can even promote autoimmune inflammation. We hypothesized that differences in the lineage specific effects of IL10 may in part explain the variability of its activity in vivo. To dissect IL10's lineage specifi actions, we generated mice conditionally deficient in the IL10-selective chain of the IL10 receptor, IL10R?. In preliminary studies, we analyzed deficiency of IL10R? on T cells, Foxp3+ regulatory T cells, B cells and macrophage in a model autoimmune disease, experimental allergic encephalomyelitis (EAE). Our findings indicated that pro- and anti- inflammatory functions of IL10 segregate in a lineage dependent manner. Further, IL10 has heterogeneous actions within a lineage, and these may have opposing effects on that lineage's pathogenicity. In this proposal we will use EAE as a model system to explore how the lineage specific effects of IL10 influence the development and progression of autoimmunity. We demonstrated that, surprisingly, the T cell response to IL10 worsened EAE. We hypothesize that IL10 helps sustain the effector T cells (Teff) responsible for immunopathology by inhibiting their terminal differentiation and promoting their survival.
In Aim 1, we will determine how IL10's actions on T cells promote immunopathology in EAE. We will address mechanisms of IL10-mediated modulation of T cell proliferation, survival, and memory in vivo, how the immune environment influences the production and effects of IL10, how IL10R signal quality, kinetics, and magnitude influence its T-specific activities, and relevant cellular sources for IL10 affecting the T cell response. In contrast to Teff, the IL10 response of Foxp3+ regulatory T cells suppressed EAE. We hypothesize that IL10 acts to support Treg longevity and suppressive capacity during inflammation.
In Aim 2 we will analyze IL10's influence on Treg survival, proliferation, maturation, and function during EAE. IL10 acts globally to limit EAE severity, yet its T cell-specific actions promote disease.
In Aim 3 we will identify and begin to characterize the cell lineages responsible for IL10's palliative effects in EAE. Dissecting how IL10 variably influences different cell lineages during autoimmunity will provide us with an improved mechanistic understanding of IL10's regulatory actions, and insights that will aid in the rational design of ne therapeutics that modulate inflammation through the IL10 pathway.
Proteins called cytokines are produced by cells of the immune system and regulate immune function. In this proposal we study a cytokine called interleukin 10 that generally limits inflammation and diseases associated with excessive inflammation, though may occasionally also promote immune responses. We will dissect how interleukin 10 differentially acts on key cell types of the immune system in order to establish how it regulates autoimmunity and to aid in the design of new interleukin 10-based immune therapies.
|Jones, Lindsay L; Alli, Rajshekhar; Li, Bofeng et al. (2016) Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation. J Immunol 196:2973-85|
|Zhao, Yunqian; Nguyen, Phuong; Ma, Jing et al. (2016) Preferential Use of Public TCR during Autoimmune Encephalomyelitis. J Immunol 196:4905-14|
|Gurung, Prajwal; Li, Bofeng; Subbarao Malireddi, R K et al. (2015) Chronic TLR Stimulation Controls NLRP3 Inflammasome Activation through IL-10 Mediated Regulation of NLRP3 Expression and Caspase-8 Activation. Sci Rep 5:14488|
|Li, Bofeng; Gurung, Prajwal; Malireddi, R K Subbarao et al. (2015) IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis. Nat Commun 6:6131|
|Li, B; Alli, R; Vogel, P et al. (2014) IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis. Mucosal Immunol 7:869-78|