The goal of this proposal is to gain insight into the molecular processes controlling yS lineage commitment and specification of effector fate. Both yS lineage commitment and specification of effector fate occur during development in the thymus;however, our understanding of the developmental cues controlling these fate decisions remains incomplete. Accumulating evidence suggests that they are governed by differences in T cell receptor (TCR) signal strength that manifest through graded repression of E box DNA binding proteins (E proteins) mediated by the E protein antagonist, IdS. Nevertheless, the E protein targets that are crucial for these fate decisions remain poorly defined. It is also unclear whether the different Y5 TCR complexes linked to alternate fate choices promote them by autonomously transducing signals of differing intensities or if they require ligand-engagement. In addressing these questions, we will exploit an ideally suited ySTCR transgenic model (KN6) whose known selecting ligand, the non-classical MHC-I nnoleculeT-10/22,CanbemanipulatedtoaltertheresultantTCRsignal.
In Aimi, wewill:employKN6tg mice as well as endogenous T-10/22 reactive yS progenitors to determine how specific ablation of the T- 10/22 ligand affects yS lineage commitment, repertoire selection, and effector function.
Aim2 seeks to understand the basis for the paradoxical observation that IdS is required for the development of VY2+ and VyS-t- yS T cells, but restrains the development of Vyi.1+ innate yS T cells. We will assess whether the expansion of Vyi.1+ innate yS T cells in the absence of IdS is an autonomous attribute of the Vyl.l A/66.3 TCR complex or requires ligand-engagement.
AimS addresses the critical unresolved question of whether y6 lineage commitment and specification of effector fate are separable or occur simultaneously. To do so, we will utilize our newly described marker of yS lineage commitment, CD7S induction. Genome wide ChlP- Seq on E protein targets will also be performed on CD73-marked cells to assemble a global regulatory network defining the commitment process. These efforts, which require the combined capabilities of all of the members of this program, promise to reveal critical new insights into how yS T cell development is controlled.

Public Health Relevance

Y5 T cells regulate inflammation, preserve epithelial barriers, and are particularty adept at killing cutaneous tumors. Accordingly, understanding the molecular processes controlling their development and function may enable their manipulation for therapeutic benefit. Moreover, our investigation of molecular effectors controlling T lineage commitment is also of fundamental importance for other developmental processes, since control of cell growth and differentiation is a recurring theme in development and transformation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI102853-01A1
Application #
8608276
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-05-15
Project End
2019-04-30
Budget Start
2014-05-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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