Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2α during inflammatory conditions

Sunao Sugita, Shintaro Horie, Orie Nakamura, Kazuichi Maruyama, Hiroshi Takase, Yoshihiko Usui, Masaru Takeuchi, Kazumi Ishidoh, Masato Koike, Yasuo Uchiyama, Christoph Peters, Yoshimi Yamamoto, Manabu Mochizuki

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

Pigment epithelium isolated from the eye possesses immunosuppressive properties such as regulatory T (Treg) cell induction; e.g., cultured retinal pigment epithelium (RPE) converts CD4+ T cells into Treg cells in vitro. RPE constitutively expresses a novel immunosuppressive factor, CTLA-2α, which is a cathepsin L (CathL) inhibitor, and this molecule acts via RPE to induce Treg cells. To clarify CTLA-2α's role in the T cell response to RPE in ocular inflammation, we used the experimental autoimmune uveitis (EAU) animal model to examine this new immunosuppressive property of RPE. In EAU models, TGF-β, but not IFN-γ inflammatory cytokines, promotes the up-regulation of the expression of CTLA-2α in RPE. Similarly, CTLA-2α via RPE was able to promote TGF-β production by the CD4 + T cells. The RPE-exposed T cells (RPE-induced Treg cells) greatly produced TGF-β and suppressed bystander effector T cells. There was less expression of CathL by the RPE-exposed T cells, and CathL-inhibited T cells were able to acquire the Treg phenotype. Moreover, CathL-deficient mice spontaneously produced Treg cells, with the increase in T cells potentially providing protection against ocular inflammation. More importantly, CD4 + T cells from EAU in CathL knockout mice or rCTLA-2α from EAU animals were found to contain a high population of forkhead box p3+ T cells. In both EAU models, there was significant suppression of the ocular inflammation. These results indicate that RPE secretes CTLA-2α, thereby enabling the bystander T cells to be converted into Treg cells via TGF-β promotion.

Original languageEnglish
Pages (from-to)5013-5022
Number of pages10
JournalJournal of Immunology
Volume183
Issue number8
DOIs
Publication statusPublished - 2009 Oct 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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