Elsevier

Immunology Letters

Volume 94, Issue 3, 15 July 2004, Pages 215-222
Immunology Letters

The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role

https://doi.org/10.1016/j.imlet.2004.05.007Get rights and content

Abstract

PD-1 and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, have been identified recently as CD28-B7 family molecules that are implicated in immune regulation. Lichen planus (LP) is a T cell-mediated chronic inflammatory mucocutaneous disease. We investigated the expression and function of PD-1 and its two ligands in LP. Immunohistochemical examination revealed the abundant expression of PD-1 and B7-H1 in infiltrating T cells and macrophages, and lower-level expression of B7-DC on macrophages in the subepithelium. Interestingly, substantial expression of B7-H1 on keratinocytes (KCs) was found close to the numerous T cell infiltrates in the subepithelium. Unstimulated cultured KCs expressed both B7-H1 and B7-DC, and their expression was upregulated by proinflammatory cytokines, particularly IFN-γ. The T-cell proliferative responses and IFN-γ production that were induced by IFN-γ-treated KCs were augmented preferentially by anti-B7-H1 mAb, but not by anti-B7-DC mAb. These results indicate the regulatory role of B7-H1 on KCs in the interactions with T cells. Our results suggest that the induction of B7-H1 on KCs may play an important role in tolerance induction in the inflamed oral mucosa and skin.

Introduction

Optimal T-cell activation requires that antigen-presenting cells (APCs) provide costimulatory signals, which can be either positive or negative [1]. During the initiation of naive T cells, the primary positive costimulatory signal is mediated via CD28, whereas signaling via CTLA-4 has a negative effect on activation [2]. Both CD28 and CTLA-4 interact with the same ligands, CD80 and CD86, which are expressed on APCs [3]. Recently, additional pairs of novel CD28-B7 family molecules have been identified: PD-1 [4] and its ligands, B7-H1 [5], which is also known as PD-L1 [6], and B7-DC [7], which is also known as PD-L2 [8]. PD-1 is expressed on activated T and B cells [4], [9], [10], and its ligands, B7-H1 and B7-DC, are inducible on activated APCs, such as dendritic cells (DCs) and macrophages [11]. B7-H1 is induced more broadly on nonlymphoid cells, such as epithelial cells [6], endothelial cells [12], [13], [14], trophoblasts [15], [16], and tumor cells [17], [18], whereas B7-DC expression is restricted to DCs and macrophages [11]. The ligation of PD-1 inhibits TCR-mediated T cell proliferation and cytokine production [6], [8], and PD-1-deficient mice develop various organ-specific autoimmune diseases [19], [20]. In addition, recent results have indicated the regulatory function of PD-1 in organ-specific immune responses, such as experimental autoimmune encephalomyelitis (EAE) [21], autoimmune diabetes [22], anti-viral immunity [14], and hapten-induced allergic skin inflammation [23]. These observations prompted us to investigate the possibility that the PD-1 pathway contributes to the pathogenesis of local, tissue-specific inflammatory responses in humans.

Lichen planus (LP) is a chronic inflammatory mucocutaneous disease, in which there is a massive local infiltration of activated T cells, increased local production of cytokines, and alternation of cell surface activation antigen expression [24]. The pathogenesis of LP may involve a T cell-mediated immunological process, in conjunction with the activation of Langerhans cells (LCs) and keratinocytes (KCs) [24], [25]. The purpose of this study was to investigate the expression and function of PD-1 and its ligands in LP. We performed immunohistochemical analyses of oral and cutaneous LP, and further investigated the functional role of B7-H1 on KCs in the interactions with T cells.

Section snippets

Tissue samples

Tissue samples were obtained from patients with oral LP (OLP, n = 10) and cutaneous LP (CLP, n = 3) and analyzed by immunohistochemistry. All of the samples were obtained as a part of diagnostic procedure with informed patient consent at Tokyo Medical and Dental University Hospital. All of the lesions were diagnosed both clinically and pathologically as LP. The clinicopathological features of the samples are summarized in Table 1. All the OLP patients demonstrated typical OLP lesions that were

Expression of PD-1, B7-H1, and B7-DC in LP

Immunohistological studies of PD-1, B7-H1, and B7-DC expression in HOM, OLP, and CLP were performed (Fig. 1 and Table 1). In HOM samples, a few CD3+ T cells were distributed in the subepithelial region and few PD-1+ cells were observed on the subepithelial mononuclear cells (Fig. 1A). In all the OLP cases, CD3+ T cells predominated in the subepithelial mononuclear cells (7.7±2.1×103 cells/mm2, 73±7%, mean ± S.D.), and CD3+ cells were distributed in the intraepithelial regions in seven patients.

Discussion

In this study, we report that: (a) PD-1 was expressed on half of subepithelial infiltrating T cells and some intraepithelial T cells in LP lesions; (b) B7-H1 was expressed on the subepithelial and intraepithelial lymphocytes and on the KCs that were located close to the T cell infiltrates; and (c) the blockade of B7-H1 on KCs induced proliferation and IFN-γ production by T cells.

LP shows a typical accumulation of T cells in both the lamina propria and epithelium, and the infiltrating T cells

Acknowledgements

We would like to thank Dr. F. Imaizumi (Tokyo Medical & Dental University, Tokyo) for the keratinocyte cultures and Ms. M. Sekiya (Tokyo Medical & Dental University) for technical assistance in preparation of CLP sections. This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology.

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