Lymphocytic tissue infiltrates in inflammatory and autoimmune diseases are the result of a dynamic balance of cell entry and exit, combined with localized proliferation and apoptosis. Whereas mechanisms of lymphocyte migration from the blood into tissues have been extensively studied and have proven to be key to the local inflammatory response, mechanisms responsible for T cell egress from extralymphoid tissues are only poorly defined. While it has been widely assumed that egress from tissues is a random process, we recently showed that lymphocyte exit from peripheral tissue is regulated and that CD4 and CD8 T cells require the expression of the chemokine receptor CCR7 for exit under non-inflammatory conditions. CCR7 and other "exit receptors" that promote T cell egress likely reduce localized lymphocyte accumulation, thereby affecting both immunosurveillance and inflammatory processes. As impaired tissue exit of inflammatory T cells could exacerbate local inflammation, exit receptors may serve as a novel target in the therapy of inflammatory diseases such as arthritis. Based on our extensive published and preliminary data, we hypothesize that T cell exit from inflamed peripheral tissues through the afferent lymph is controlled by both CCR7-dependent and -independent mechanisms, and that the relative importance of CCR7 and alternative exit receptors is determined by the nature and chronicity of the local inflammatory response. In this proposal, employing mouse and large animal models, we will test the role of CCR7 in T cell egress from inflamed skin as well as identify chemoattractant receptors mediating CCR7-independent T cell exit that operate under chronic inflammatory condition. Moreover, we propose to study the regulation of exit receptors on both bystander as well as antigen-specific memory/effector T cells recirculating through an inflammatory lesion. Importantly, using an established model of delayed type hypersensitivity, we will test the hypothesis that the regulated expression of tissue T cell CCR7 and other exit receptors modulate the initiation, maintenance and/or resolution of tissue inflammation. Moreover, we predict that the obtained results will serve as a proof of principle that targeting of T exit receptors can be used therapeutically to modulate the magnitude of inflammatory infiltrates in the treatment of autoimmune and inflammatory diseases.

Public Health Relevance

Immune cells are the main cells responsible for tissue destruction and inflammation in arthritis and other chronic inflammatory diseases. Our goal is to determine the mechanisms by which immune cells leave inflamed tissues. Based on the new knowledge, therapies can be developed that force immune cells out of the tissue to stop ongoing inflammation and associated pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056730-05
Application #
8477130
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Cibotti, Ricardo
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$325,037
Indirect Cost
$121,889
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Francesca Diane M; Kenngott, Elisabeth E; Schröter, Micha F et al. (2014) Timed action of IL-27 protects from immunopathology while preserving defense in influenza. PLoS Pathog 10:e1004110
Geherin, Skye A; Wilson, R Paul; Jennrich, Silke et al. (2014) CXCR4 is dispensable for T cell egress from chronically inflamed skin via the afferent lymph. PLoS One 9:e95626
Geherin, Skye A; Lee, Michael H; Wilson, R Paul et al. (2013) Ovine skin-recirculating ýýýý T cells express IFN-ýý and IL-17 and exit tissue independently of CCR7. Vet Immunol Immunopathol 155:87-97
Brown, Meghan N; Fintushel, Sarah R; Lee, Michael H et al. (2010) Chemoattractant receptors and lymphocyte egress from extralymphoid tissue: changing requirements during the course of inflammation. J Immunol 185:4873-82