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.
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.
|Cao, Lauren Y; Chung, Jin-Sung; Teshima, Takahiro et al. (2016) Myeloid-Derived Suppressor Cells in Psoriasis Are an Expanded Population Exhibiting Diverse T-Cell-Suppressor Mechanisms. J Invest Dermatol 136:1801-10|
|Chung, Jin-Sung; Tamura, Kyoichi; Akiyoshi, Hideo et al. (2014) The DC-HIL/syndecan-4 pathway regulates autoimmune responses through myeloid-derived suppressor cells. J Immunol 192:2576-84|
|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 134:2839-42|
|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 134:2784-94|
|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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