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.
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.
|Lee, Sang-Yun; Coffey, Francis; Fahl, Shawn P et al. (2014) Noncanonical mode of ERK action controls alternative ?? and ?? 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|