Retinal Pigment Epithelium-Derived CTLA-2α Induces TGFβ-Producing T Regulatory Cells

Sugita, Sunao; Horie, Shintaro; Nakamura, Osamu; Futagami, Yuri; Takase, Hiroshi; Keino, Hiroshi; Aburatani, Hiroyuki; Katunuma, Nobuhiko; Ishidoh, Kazumi; Yamamoto, Yasutake; Mochizuki, Manabu

doi:10.4049/jimmunol.181.11.7525

Cited by 106 publications

(130 citation statements)

References 48 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…The harvested T cells contained Յ0.99% cytokeratin ϩ RPE, whereas the cultured RPE did not contain any CD45 ϩ , F4/80 ϩ , or MHC class II ϩ cells, as has been previously reported (13).…”

Section: Preparation Of Primary Cultures Of Rpe and Rpe-induced Treg supporting

confidence: 52%

“…When the RPE encounters T cells, these secreted proteins can selectively inhibit the CathL on the effector T cells (13). The RPE-CTLA-2␣-controlled CathL activity and CathL-inhibited T cells were able to acquire the Treg phenotype in vitro (13). Moreover, the CTLA-2␣, which affects Treg cell induction, occurs via the TGF-␤ signaling pathway, because the CTLA-2␣ can promote activation of TGF-␤ in the eye.…”

mentioning

confidence: 99%

“…In previous eye studies, retinal pigment epithelium (RPE) has been found to constitutively express CTLA-2␣. When the RPE encounters T cells, these secreted proteins can selectively inhibit the CathL on the effector T cells (13). The RPE-CTLA-2␣-controlled CathL activity and CathL-inhibited T cells were able to acquire the Treg phenotype in vitro (13).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Acquisition of T Regulatory Function in Cathepsin L-Inhibited T Cells by Eye-Derived CTLA-2α during Inflammatory Conditions

Sugita

Horie

Nakamura

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Preparation Of Primary Cultures Of Rpe and Rpe-induced Treg supporting

confidence: 52%

mentioning

confidence: 99%

See 1 more Smart Citation

Acquisition of T Regulatory Function in Cathepsin L-Inhibited T Cells by Eye-Derived CTLA-2α during Inflammatory Conditions

Sugita

Horie

Nakamura

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The eye is an immune privileged site with potent suppressive mechanisms, partly involving Treg cells that differentiate locally from naive conventional T cells (45)(46)(47). Tolerance to autoantigens expressed in the eye is broken during uveitis, even though the tissue contains substantial amounts of Treg cells, at least in mouse models [our work and the one of others (48)].…”

Section: Discussionmentioning

confidence: 99%

Treatment of Uveitis by In Situ Administration of Ex Vivo–Activated Polyclonal Regulatory T Cells

Grégoire

Terrada

Martin

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

CD4+CD25+Foxp3+ regulatory T (Treg) cell therapy is a promising approach for the treatment of autoimmune diseases. To be effective, Treg cells should be in an activated state in the target tissue. This can be achieved by systemic administration of Ag-specific Treg cells, which are difficult to produce in conditions that can be translated to the clinic. In this paper, we propose an alternative approach consisting of in situ injection of preactivated polyclonal Treg cells that would exert bystander suppression in the target tissue. We show that polyclonal Treg cells suppressed uveitis in mice as efficiently as Ag-specific Treg cells but only when preactivated and administered in the vitreous. Uveitis control was correlated with an increase of IL-10 and a decrease of reactive oxygen species produced by immune cell infiltrates in the eye. Thus, our results reveal a new mechanism of Treg cell–mediated suppression and a new Treg cell therapy approach.

show abstract

“…The RPE suppress immunity by both cell surface and soluble molecules. On the surface of RPE are FasL, PD-L1, CTLA2, and TGF-β2 that with contact suppress effector T cell while inducing Treg cell activity [13][14][15][16][17]. In addition, soluble factors TGF-β2, Thrombospondin-1, and α-MSH further promote Treg cell activation [1,4].…”

Section: Discussionmentioning

confidence: 99%

Retinal Pigment Epithelial Cell Line Suppression of Phagolysosome Activation

Taylor

Dixit

2015

IJOES

View full text Add to dashboard Cite

The eye is an immune privileged tissue with multiple mechanisms of immunosuppression to protect the light gathering tissues from the damage of inflammation. One of theses mechanisms involves retinal pigment epithelial cell suppression of phagosome activation in macrophages. The objective of this work is to determine if the human RPE cell line ARPE-19 is capable of suppressing the activation of the phagolysosome in macrophages in a manner similar to primary RPE. The conditioned media of RPE eyecups, sub-confluent, just confluent cultures, or established confluent cultures of human ARPE-19 cells were generated. These condition media were used to treat macrophages phagocytizing pHrodo bioparticles. After 24 hours incubation the macrophages were imaged by fluorescent microscopy, and fluorescence was measured. The fluorescent intensity is proportional to the amount of bioparticles phagocytized and are in an activated phagolysosome. The conditioned media of in situ mouse RPE eyecups significantly suppressed the activation of phagolysosome. The conditioned media from cultures of human ARPE-19 cells, grown to sub-confluence (50%) or grown to confluence had no effect on phagolysosome activation. In contrast, the conditioned media from established confluent cultures significantly suppressed phagolysosome activation. The neuropeptides alpha-MSH and NPY were depleted from the conditioned media of established confluent ARPE-19 cell cultures. This depleted conditioned media had diminished suppression of phagolysosome activation while promoting macrophage cell death. In addition, the condition media from cultures of ARPE-19 monolayers wounded with a bisecting scrape was diminished in suppressing phagolysosome activation. This technical report suggests that like primary RPE monolayers, established confluent cultures of ARPE-19 cells produce soluble factors that suppress the activation of macrophages, and can be used to study the molecular mechanisms of retinal immunobiology. In addition, the results further demonstrate the importance of an intact monolayer of RPE cells to modulate immune cell activity within the eye.

show abstract

Retinal Pigment Epithelium-Derived CTLA-2α Induces TGFβ-Producing T Regulatory Cells

Cited by 106 publications

References 48 publications

Acquisition of T Regulatory Function in Cathepsin L-Inhibited T Cells by Eye-Derived CTLA-2α during Inflammatory Conditions

Acquisition of T Regulatory Function in Cathepsin L-Inhibited T Cells by Eye-Derived CTLA-2α during Inflammatory Conditions

Treatment of Uveitis by In Situ Administration of Ex Vivo–Activated Polyclonal Regulatory T Cells

Retinal Pigment Epithelial Cell Line Suppression of Phagolysosome Activation

Contact Info

Product

Resources

About