Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions.
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-2alpha, which is a cathepsin L (CathL) inhibitor, and this molecule acts via RPE to induce Treg cells. To clarify CTLA-2alpha'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-beta, but not IFN-gamma inflammatory cytokines, promotes the up-regulation of the expression of CTLA-2alpha in RPE. Similarly, CTLA-2alpha via RPE was able to promote TGF-beta production by the CD4(+) T cells. The RPE-exposed T cells (RPE-induced Treg cells) greatly produced TGF-beta 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-2alpha 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-2alpha, thereby enabling the bystander T cells to be converted into Treg cells via TGF-beta promotion.
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine and Dental Sciences, Tokyo, Japan. sunaoph@tmd.ac.jp
Sunao
S
Sugita
Shintaro
S
Horie
Orie
O
Nakamura
Kazuichi
K
Maruyama
Hiroshi
H
Takase
Yoshihiko
Y
Usui
Masaru
M
Takeuchi
Kazumi
K
Ishidoh
Masato
M
Koike
Yasuo
Y
Uchiyama
Christoph
C
Peters
Yoshimi
Y
Yamamoto
Manabu
M
Mochizuki
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000276:immunology; D004195:Disease Models, Animal; D005123:Eye / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005136:Eye Proteins / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000276:immunology*; D012177:Retinol-Binding Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D014605:Uveitis / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D000943:Antigens, Differentiation; D056668:Cathepsin L; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D005136:Eye Proteins; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D012177:Retinol-Binding Proteins; D016212:Transforming Growth Factor beta; D000099214:Retinol-Binding Proteins, Interstitial; C498833:Foxp3 protein, mouse; C102076:cytotoxic T-lymphocyte antigen-2, mouse; C534278:Ctsl protein, mouse