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.
|Fahl, Shawn P; Coffey, Francis; Kain, Lisa et al. (2018) Role of a selecting ligand in shaping the murine ??-TCR repertoire. Proc Natl Acad Sci U S A 115:1889-1894|
|Zarin, Payam; In, Tracy Sh; Chen, Edward Ly et al. (2018) Integration of T-cell receptor, Notch and cytokine signals programs mouse ?? T-cell effector differentiation. Immunol Cell Biol 96:994-1007|
|Zhang, Baojun; Jiao, Anjun; Dai, Meifang et al. (2018) Id3 Restricts ?? NKT Cell Expansion by Controlling Egr2 and c-Myc Activity. J Immunol 201:1452-1459|
|Murre, Cornelis (2018) 'Big bang' of B-cell development revealed. Genes Dev 32:93-95|
|Roy, Sumedha; Moore, Amanda J; Love, Cassandra et al. (2018) Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection. Front Immunol 9:42|
|Chisolm, Danielle A; Savic, Daniel; Moore, Amanda J et al. (2017) CCCTC-Binding Factor Translates Interleukin 2- and ?-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs. Immunity 47:251-267.e7|
|Li, Jia; Roy, Sumedha; Kim, Young-Mi et al. (2017) Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors. J Immunol 198:3136-3148|
|Zhu, Yina; Gong, Ke; Denholtz, Matthew et al. (2017) Comprehensive characterization of neutrophil genome topology. Genes Dev 31:141-153|
|Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Kenian et al. (2017) The E-Id Protein Axis Specifies Adaptive Lymphoid Cell Identity and Suppresses Thymic Innate Lymphoid Cell Development. Immunity 46:818-834.e4|
|Moore, Amanda J; In, Tracy Sh; Trotman-Grant, Ashton et al. (2017) A key role for IL-7R in the generation of microenvironments required for thymic dendritic cells. Immunol Cell Biol 95:933-942|
Showing the most recent 10 out of 23 publications