Because T cell activation is a highly regulated event with crucial consequences to the host, it is important to understand mechanisms that promote as well as down-regulate it. We discovered DC-HIL, a type I transmembrane protein expressed constitutively at high levels by epidermal Langerhans cells and dendritic cells (DC). Soluble DC-HIL bound to activated (but not naive) T cells, indicating that expression of its T cell ligand (DC-HIL-L) requires activation. In T cell activation assays, immobilized DC-HIL acted as a negative agonist, markedly attenuating T cell proliferation and IL-2 secretion triggered by signaling via the T cell receptor. By contrast, soluble DC-HIL augmented the mixed lymphocyte reaction and exacerbated contact hypersensitivity (CH) when injected intraperitoneally into mice during hapten-challenge (but not during hapten-priming); herein, DC-HIL acted as an antagonist interfering with binding of DC-HIL to DC-HIL-L. We hypothesize that the DC-HIL/DC-HIL-L pathway transmits a potent inhibitory signal to activated T cells and plays an important role in down-regulating effector T cell responses.
Our specific aims are to: (1) Determine whether DC-HIL expression on DC modulates antigen presenting cell function in vitro. We will examine the ability of DC engineered genetically to over-express or silence DC-HIL, to activate T cells. (2) Characterize the inhibitory function of DC-HIL/DC-HIL-L pathway in vivo using the CHmodel. We will: identify DC-HIL- or DC-HIL-L-expressing cells in skin and lymph nodes (LN) of hapten-sensitized mice; characterize LN T cells in sensitized mice treated with soluble DC-HIL; compare DC-HIL/DC-HIL-L and PD-1/PD-L pathways for potency, synergy, and kinetics of down-regulated T cell activation; and examine DC-HIL knockout mice for phenotypic and functional changes including CH responses. (3) Identify DC-HIL-L on activated T cells by biochemical methods and an expression cloning strategy. Our results are likely to show great promise for DC-HIL and DC-HIL-L as potential therapeutic targets for immunologic or pharmacologic modulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064927-02
Application #
7035790
Study Section
Special Emphasis Panel (ZRG1-ACTS (01))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2005-04-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2006
Total Cost
$342,752
Indirect Cost
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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Turrentine, Jake; Chung, Jin-Sung; Nezafati, Kaveh et al. (2014) DC-HIL+ CD14+ HLA-DR no/low cells are a potential blood marker and therapeutic target for melanoma. J Invest Dermatol 134:2839-2842
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Chung, Jin-Sung; Tamura, Kyoichi; Cruz Jr, Ponciano D et al. (2014) DC-HIL-expressing myelomonocytic cells are critical promoters of melanoma growth. J Invest Dermatol 134:2784-2794
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; Tomihari, Mizuki; Tamura, Kyoichi et al. (2013) The DC-HIL ligand syndecan-4 is a negative regulator of T-cell allo-reactivity responsible for graft-versus-host disease. Immunology 138:173-82
Das, Shinjita; Ariizumi, Kiyoshi; Cruz Jr, Ponciano D (2012) T-cell inhibitors: a bench-to-bedside review. Dermatitis 23:195-202
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

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