title: Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells.
abstract: T cells that encounter ocular pigment epithelium in vitro are inhibited from undergoing TCR-triggered activation, and instead acquire the capacity to suppress the activation of bystander T cells. Because retinal pigment epithelial (RPE) cells suppress T cell activation by releasing soluble inhibitory factors, we studied whether soluble factors also promote the generation of T regulatory (Treg) cells. We found that RPE converted CD4(+) T cells into Treg cells by producing and secreting CTLA-2alpha, a cathepsin L (CathL) inhibitor. Mouse rCTLA-2alpha converted CD4(+) T cells into Treg cells in vitro, and CTLA-2alpha small interfering RNA-transfected RPE cells failed to induce the Treg generation. RPE CTLA-2alpha induced CD4(+)CD25(+)Foxp3(+) Treg cells that produced TGFbeta in vitro. Moreover, CTLA-2alpha produced by RPE cells inhibited CathL activity in the T cells, and losing CathL activity led to differentiation to Treg cells in some populations of CD4(+) T cells. In addition, T cells in the presence of CathL inhibitor increased the expression of Foxp3. The CTLA-2alpha effect on Treg cell induction occurred through TGFbeta signaling, because CTLA-2alpha promoted activation of TGFbeta in the eye. These results show that immunosuppressive factors derived from RPE cells participate in T cell suppression. The results are compatible with the hypothesis that the eye-derived Treg cells acquire functions that participate in the establishment of immune tolerance in the posterior segment of the eye.
authors.affiliation: Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan. sunaoph@tmd.ac.jp
authors.forename: Sunao
authors.initials: S
authors.lastname: Sugita
authors.forename: Shintaro
authors.initials: S
authors.lastname: Horie
authors.forename: Orie
authors.initials: O
authors.lastname: Nakamura
authors.forename: Yuri
authors.initials: Y
authors.lastname: Futagami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Keino
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ishidoh
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Manabu
authors.initials: M
authors.lastname: Mochizuki
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D056668:Cathepsin L; D002403:Cathepsins / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; C102076:cytotoxic T-lymphocyte antigen-2, mouse; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse