Our long-term goal is to understand the molecular basis for the importance of dendritic antigen presenting cells in generating immune responses relevant to skin, hoping our discoveries lead to better treatments for inflammatory diseases. Having discovered a unique T cell inhibitory pathway, composed of DC-HIL on antigen presenting cells (APC) and its ligand syndecan-4 (SD-4) on activated T cells, that shares overlapping features with other known APC/T cell pairs of inhibitory molecules, but is distinguished by the ability to deactivate effector/memory T cells while sparing regulatory T cells, we now wish to: (1) elucidate signals within T cells triggered by binding of DC-HIL to SD-4 with a focus on CD148 phosphatase activity in human cells;(2) develop strategies employing toxin-bearing DC-HIL to treat SD-4+ T cell-mediated skin inflammation using mouse models of contact hypersensitivity;and (3) validate the differential effect of DC-HIL on effector vs. regulatory T cells in vivo using mouse models of lethal acute graft-vs.-host disease. Our new findings, in turn, should lead to application of the DCHIL/SD-4 pathway for biologic and/or pharmacologic benefit.

Public Health Relevance

We discovered and have characterized a unique T cell inhibitory pathway composed of DC-HIL on antigen presenting cells (APC) and its ligand syndecan- 4 (SD-4) on activated T cells. This pathway is distinguished by its ability to deactivate effector/memory T cells while sparing regulatory T cells. Our proposal will: elucidate signals within T cells triggered by DC-HIL/SD-4 ligation;develop strategies employing toxin-bearing DC-HIL to treat SD-4+ T cell-mediated skin inflammation;and validate the differential effect of DC-HIL on effector vs. regulatory Tcells in vivo. Our new findings should lead to application of the DC- HIL/SD-4 pathway for biologic and/or pharmacologic benefit.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064927-08
Application #
8391256
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mallia, Conrad M
Project Start
2005-04-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$369,914
Indirect Cost
$137,264
Name
University of Texas Sw Medical Center Dallas
Department
Dermatology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Baker, Lauren; Litzner, Brandon; Le, Elizabeth N et al. (2013) Ectopic periorbital dermatitis and mycosis fungoides-like dermatitis due to propolis. Dermatitis 24:328-9
Nezafati, Kaveh A; Carroll, Bryan; Storrs, Frances J et al. (2013) Making contact for contact dermatitis: a survey of the membership of the American Contact Dermatitis Society. Dermatitis 24:47-9
Chung, Jin-Sung; Cruz Jr, Ponciano D; Ariizumi, Kiyoshi (2011) Inhibition of T-cell activation by syndecan-4 is mediated by CD148 through protein tyrosine phosphatase activity. Eur J Immunol 41:1794-9
Chung, Jin-Sung; Shiue, Lisa H; Duvic, Madeleine et al. (2011) Sezary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-beta on the cell surface. Blood 117:3382-90
Chung, Jin-Sung; Bonkobara, Makoto; Tomihari, Mizuki et al. (2009) The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. Eur J Immunol 39:965-74
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