Src homology 2 domain‐containing protein tyrosine phosphatase substrate 1 regulates the induction of Langerhans cell maturation

Abstract

Recently, we reported that Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1) plays an important role in the migration of Langerhans cells (LC). Here, we show that SHPS-1 is involved in the maturation of LC. Immunofluorescence analysis on epidermal sheets for I-A or CD86 revealed that LC maturation induced by 2,4-dinitro-1-fluorobenzene (DNFB) or by TNF-a was inhibited by pretreatment with an anti-SHPS-1 monoclonal antibody (mAb) or with CD47-Fc fusion protein, a ligand for SHPS-1. Further, FACS analysis demonstrated that I-A + LC that had emigrated from skin explants expressed CD80 or CD86, whereas CD47-Fc protein reduced CD80 high+ or CD86 high+ cells. CD47-Fc protein also reduced the upregulation of surface CD80 or CD86 by LC remaining in the skin explants. In SHPS-1 mutant mice, we observed that the up-regulation of surface CD86 and CCR7 by LC induced by DNFB as well as that of surface CD80 and CD86 by LC in skin explants was attenuated. Finally, contact hypersensitivity (CHS) response was suppressed in SHPS-1 mutant mice and in wild-type mice treated with an anti-SHPS-1 mAb. These observations indicate that SHPS-1 plays an important role in the maturation of LC ex vivo and in vivo, and that SHPS-1-CD47 interaction may negatively regulate CHS. IntroductionDC are potent antigen-presenting cells that play a crucial role in the initiation of immune responses to pathogens. Langerhans cells (LC) are specialized immature DC in the skin that reside in the suprabasal layers of the epidermis. When LC encounter exogenous antigens, including haptens and microorganisms, they capture and process them to generate MHC/peptide complexes on their surface. LC migrate from the epidermis to draining lymphoid tissues in order to initiate naive T cells and to present the MHC/peptide complexes to Correspondence: Dr. Tatsuya Horikawa, Division of Dermatology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017Japan Fax:+81-78-382-6149 e-mail: thorikaw@med.kobe-u.ac.jp Received 12/1/06Revised 13/9/06 Accepted 19/10/06 [DOI 10.1002/eji.200635864] Key words: Contact hypersensitivity Á Langerhans cells Á Maturation Á Src homology 2 domaincontaining protein tyrosine phosphatase substrate 1Abbreviations: CCR7: CC chemokine receptor 7 Á CHS: contact hypersensitivity Á DNFB: 2,4-dinitro-1-fluorobenzene Á LC: Langerhans cell Á SHPS-1: Src homology 2 domaincontaining protein tyrosine phosphatase substrate 1 Á SIRP a1: signal-regulatory protein a1 and . In mice, SHPS-1 is expressed in myeloid cells, including monocytes, macrophages and DC [25]. SHPS-1 is a transmembrane glycoprotein whose extracellular domain comprises three immunoglobulin-like domains with multiple N-linked glycosylation sites, while the cytoplasmic domain of SHPS-1 contains four tyrosine residues that form two ITIM [26]. SHPS-1 was initially discovered as a tyrosine-phosphorylated transmembrane protein that binds SHP-1 or SHP-2. IAP/CD47, an integrin-associated...

Essential roles of SHPS-1 in induction of contact hypersensitivity of skin

“…The CHS response to DNFB was significantly reduced in female SHPS-1 mutant mice compared with that in WT females (Fig. 1A), as described previously [25]. In contrast, the CHS response in CD47-deficient mice was virtually identical to that in WT mice (Fig.…”

“…In contrast, CD47 is expressed in a variety of hematopoietic cells including red blood cells and T cells [18]. We have recently shown that mice expressing a mutant form of SHPS-1 that lacks most of the cytoplasmic region are resistant to 2,4-dinitro-1-fluorobenzene (DNFB)-induced CHS as well as to experimental autoimmune encephalomyelitis (EAE) [25,26]. In addition, the production of IL-17 by T cells from SHPS-1 mutant mice exposed to the antigens responsible for the induction of these conditions was markedly impaired, suggesting that SHPS-1 expressed on the surface of LCs or DCs is essential for priming of naive T cells as well as for their Th17 differentiation during the development of CHS or EAE.…”

Resistance to Experimental Autoimmune Encephalomyelitis and Impaired T Cell Priming by Dendritic Cells in Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Mutant Mice

“…In addition, it was recently shown that delayed-type hypersensitivity to 2,4-dinitro-1-fluorobenzene, which is also thought to be mediated by Th1 cells, is markedly diminished in CD47-deficient mice (43). Conversely, we found that such delayed-type hypersensitivity is greatly reduced in extent in SHPS-1 mutant mice (44). Moreover, ligation of CD47 on T cells is thought to generate costimulatory signals for T cell activation (45).…”

Dermal Dendritic Cells, and Not Langerhans Cells, Play an Essential Role in Inducing an Immune Response

“…Murine epidermal sheets were prepared as described previously (22). After fixation, the sheets were incubated at room temperature overnight with purified anti-mouse Langerin or biotin-conjugated anti-mouse I-A/I-E.…”