A new approach to homeostatic maintenance of dendritic epidermal T cells

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DESCRIPTION (provided by applicant): Homeostatic maintenance of somatic tissues typically requires replacement of damaged or aged cells by young cells generated from progenitors or somatic stem cells. However, not all tissue types are maintained in such a way. Dendritic Epidermal T Cells (DETC) are skin resident ?¿ T cells, which are exclusively derived from fetal thymus through V(D)J recombination of the T cell antigen receptor (TCR) genes but are maintained as a homogeneous population expressing a canonical ?¿TCR in the skin epithelium throughout postnatal life. DETC play important roles in epithelium barrier surveillance, tumor surveillance, and wound healing. The entire DETC population is self-sustained throughout life, yet the lifespan and regenerative behavior of individual DETC remain elusive. To facilitate genetic dissection of ?¿ T cells, our lab now produced the first ?¿ lineage specific Cre strain. Lineage specific conditional gene activation or deletion can be achieved in a temporally and spatially controlled manner through tamoxifen treatment. This newly established genetic tool provides an unprecedented opportunity for us to track and genetically manipulate DETC during postnatal life. We will use this genetic tool to explore two fundamental issues concerning homeostatic maintenance of DETC in the adult skin: 1) do DETC expand and/or regenerate uniformly during homeostatic maintenance and 2) the necessity of TCR signaling in either long-term maintenance of DETC or routine function such as wound healing. First, we will combine the inducible Cre with a multi-color fluorescent reporter to label DETC and track their clonal behavior in live mice. Second, we will use the inducible Cre system to disrupt the TCR signaling pathway through conditional gene knockout. The homogeneity of DETC TCR supports the idea that antigens play an important role in the initial selection of DETC. Whether TCR signaling is needed for long-term homeostatic maintenance of DETC is not known. The proposed study will lay the groundwork for genetic analysis of regulatory pathways underpinning homeostatic maintenance of DETC in adult life. The study of DETC also serves as an excellent model for understanding the fundamental rules of tissue maintenance in adult life, particularly in the case where tissue maintenance is independent of progenitor or somatic stem cells.