T cells belonging to the y?-lineage have been shown to serve a unique and critical role within the immune system. y? T cells are widely distributed throughout mucosal and epithelial cell-rich tissues and are an important early source of IL-17 in response to a number of pathogens, recruiting granulocytes to the site of inflammation. However, how y? T cells acquire the ability to respond as IL-17-producing cells prior to antigen exposure remains unclear. Additionally, how y? T cells become specified and assigned to IL-17 or interferon-y (IFNy) effector fates remains to be fully elucidated. Recent evidence supports the notion that T cell receptor (TCR) signals affect the type of effector function that y? T cells adopt within the thymus, such as becoming interferon-y (IFNy), IL-4 or IL-17 producing cells. Given the critical importance of Notch signaling throughout T cell differentiation, we hypothesized that the final differentiation and effector function selection by y? T cells is guided by Notch receptor-ligand interactions, which influence the generation of IFNy vs. IL-17 producing cells. We will take advantage of the in vitro model system that we have previously established to elucidate the roles for TCR, Notch and cytokine signals in determining the final effector function of y? T cells, and gain insight into the molecular basis for these selections by assembling global gene regulatory networks.
Our aims are: 1) to address the role of Notch receptor signaling in y? T cell effector differentiation;2) to address the role of cytokine receptor signaling in y? T cell effector differentiation;and, 3) to determine the role of E-proteins, together with Notch and cytokine signals, in specifying y? T cell effector function. Taken together, our joint experimental approach and findings will provide important insights into the molecular processes controlling y? T cell development and function, which would not be possible without the combined expertise provided by all members of this program.
T-cells belonging to the yd-lineage serve a unique and important role within the immune system, with yd T cells involved in functions that include wound repair, cancer cell lysis, and protection against bacterial infections. Therefore, a greater understanding of how the development of yd T cells is controlled at the molecular level may enable the manipulation of their production or function for therapeutic benefit.
|Zhang, Baojun; Jia, Qingzhu; Bock, Cheryl et al. (2016) Glimpse of natural selection of long-lived T-cell clones in healthy life. Proc Natl Acad Sci U S A 113:9858-63|
|Wiest, David L (2016) Development of Î³Î´ T Cells, the Special-Force Soldiers of the Immune System. Methods Mol Biol 1323:23-32|
|Chen, Shuwen; Miyazaki, Masaki; Chandra, Vivek et al. (2016) Id3 Orchestrates Germinal Center B Cell Development. Mol Cell Biol 36:2543-52|
|Zhang, Baojun; Wu, Jianxuan; Jiao, Yiqun et al. (2015) Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells. J Immunol 195:4282-91|
|Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2015) The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis. Genes Dev 29:409-25|
|Zarin, Payam; Chen, Edward L Y; In, Tracy S H et al. (2015) Gamma delta T-cell differentiation and effector function programming, TCR signal strength, when and how much? Cell Immunol 296:70-5|
|Roy, Sumedha; Zhuang, Yuan (2015) Orchestration of invariant natural killer T cell development by E and Id proteins. Crit Rev Immunol 35:33-48|
|Lee, Sang-Yun; Coffey, Francis; Fahl, Shawn P et al. (2014) Noncanonical mode of ERK action controls alternative Î±Î² and Î³Î´ T cell lineage fates. Immunity 41:934-46|
|Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2014) Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol 15:767-76|