Dysregulation of innate and conventional T cells is a contributing factor for many inflammatory autoimmune diseases in humans, like multiple sclerosis, colitis and rheumatoid arthritis as well as susceptibility to infections and cancers. Our lab is interested in understanding the metabolic mechanisms governing the immune fate of CD4 (T helper) and CD8 (T killer) cells and to identify the factors or pathways that can manipulate these metabolic mechanisms. We use a multidisciplinary approach involving immunologic, biochemical and metabolic assays to identify various signaling pathways and to decipher the role of these factors in T cell fate decision during pathological conditions. We use T-cell specific genetically modified mice strains as tools to investigate in vivo consequences.
On going projects
Keap1-Nrf2 as metabolic checkpoint for CD4 T-cell effector responses in inflammation
My research will focus on deciphering the role of Keap1-Nrf2 complex in the T effector cell differentiation and in T cell mediated inflammation by acting as a metabolic checkpoint for maintaining Th17-Treg balance. Thus far, anti-oxidant independent roles of Keap1 and Nrf2 are not known in T cells. Further, the ability of Keap1-Nrf2 system to alter cellular metabolism in T cells has not been reported as well. Using mice strains that are deficient of Keap1, Nrf2, or both, we investigate the individual contributions of Keap1 and Nrf2. Much remains to be explored about how Nrf2 regulates the switch between glucose and glutamine metabolism in CD4 T cells to control CD4 T cell activation, proliferation and function. With immune-metabolism being the center of therapeutic research recently, the proposed research, according to me, has great potential. We are examining the in vivo significance of Nrf2-mediated CD4 T-cell metabolism and effector functions in inflammatory diseases like multiple sclerosis and IBD using mouse models.
Role of Antioxidant protein Nrf2 in metabolism and anti-tumor activities of cytotoxic CD8+ T-cells.
Upon antigen-stimulation, activated CD8+ T-cells proliferate and differentiate into cytotoxic T-cells (CTLs) which target tumors and virally infected cells. CTLs are used in adoptive cell therapy to target and kill tumor cells. Studying the underlying cellular processes that affect CTL cytotoxicity and expansion is important for improving the current adoptive cell therapies as well as to design novel immunotherapies. Our goal is to decipher the contribution of the antioxidant pathway on the activation of CD8+ T-cells and CTL responses using genetically-modified mice and mouse tumor models. Nrf2 is known to regulate cell metabolism in cancer cells but its role in CD8 T-cell metabolism and its contribution to anti-tumor functions is unexplored. Using flow cytometry, biochemical assays and Seahorse analysis we are investigating if Nrf2 cross talks with and modulates mTORC1 signaling to change the anti-tumor responses of CD8+ T-cells. Future studies will test if Nrf2 suppressors can be used therapeutically to increase the anti-tumor responses of CD8+ T-cells.
Role of ROS and cell metabolism in aging-associated changes in NKT cell inflammatory and tumor-surveillance functions.
The rate and/or extent of age-associated immune dysfunction, called ‘immunosenescence’ is a part of aging phenomenon and can be defined as a state of relaxed immune function. Although well defined in conventional T cells, a critical gap remains in our understanding about immunosenescence and the mechanisms that contribute to them in innate T cells like NKT cells. PLZF is a critical transcription factor for innate functions of NKT cells and we reported that it regulates ROS levels (Kim et al., 2017) and metabolism of NKT cells (Kumar et al., 2019) We are interested in investigating if change in ROS and or metabolism with age is responsible for the decreased inflammatory and anti-tumor responses in aging NKT cells leading to increased incidence of bacterial infections and tumors in elderly.
Pyaram et al.,Cell Reports (2019)
