With the proposed Research Scientist Development Award, the applicant will build upon her prior experience in antigen and chemokine regulation of T cell migration and immunity to study T cell recirculation using in vivo models of skin inflammation. The laboratory of Andrew D. Luster, MD, PhD, at Massachusetts General Hospital will provide a stimulating environment to further the candidate's scientific development toward achieving her ultimate goal of independent investigation. The proposed study will provide the applicant with the opportunity to examine the interplay of chemokines in regulating the migratory fate of T cells in inflamed skin. Both T cell entry into tissues from the bloodstream and T cell exit from tissues into afferent lymph control the accumulation of lymphocytes at peripheral sites and their participation in immune/inflammatory reactions. The roles of several individual chemokines in directing the traffic of T cell entry and exit from the skin have been characterized. However, the interplay between different chemokine signals in controlling the transit of T cells through skin remains completely unknown. Here, we hypothesize that a balance in chemokine entry, retention, and exit signals regulates the accumulation of effector/memory T cells within skin. In these proposed studies, we will use delayed type hypersensitivity and allergic dermatitis models to 1) Investigate the mechanisms that regulate the accumulation of effector/memory T cells in inflamed skin. We will track the migration of responding T cells by labelling cutaneous T cells in vivo with CFSE and determine the chemokine receptor expression profiles of CFSE+ T cells that remain in the skin, versus those that continue to migrate through the skin to draining lymph nodes;2) Determine the consequence of effector/memory T cell antigen recognition in peripheral tissues on their expression of chemokine receptors and their retention in skin versus migration into afferent lymph;3) Attempt to override the balance in chemokine receptor responsiveness using genetically altered T cells and mice that either lack or overexpress chemokine receptors or chemokine ligands. Results from these studies should further elucidate the mechanisms that regulate T cell transit through tissues and might benefit the treatment of pathological conditions in which large T cell infiltrates accumulate inappropriately in peripheral tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR053715-04
Application #
7590369
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Cibotti, Ricardo
Project Start
2006-04-12
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$128,520
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Bromley, Shannon K; Larson, Ryan P; Ziegler, Steven F et al. (2013) IL-23 induces atopic dermatitis-like inflammation instead of psoriasis-like inflammation in CCR2-deficient mice. PLoS One 8:e58196
Bromley, Shannon K; Yan, Sha; Tomura, Michio et al. (2013) Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J Immunol 190:970-6