Tolerogenic dendritic cells suppress murine corneal allograft rejection by modulating CD28/CTLA‐4 expression on regulatory T cells

Abstract

Anterior chamber-associated immune deviation (ACAID) is initiated when dendritic cells (DCs) capture intraocular antigen and induce regulatory T cells (Tregs) in the spleen. We investigated whether DCs could be used as an immunotherapy to prevent murine corneal allograft rejection by inducing Tregs. Bone marrow-derived DCs (BMDCs) were differentiated with transforming growth factor-β2 (TGF-β2) in the presence of donor-derived allopeptide in vitro (TGFβ2-DCs), and adoptively transferred to BALB/c mice. Three days later a corneal allograft transplant was carried out. Graft rejection, as well as the number and the phenotype of splenic Tregs, were determined after transplant. CD86, CD80, CD40 were present, and MHC class II expression were significantly reduced on TGFβ2-DCs compared to BMDCs not exposed to TGF-β2. TGFβ2-DCs increased the number of splenic Tregs (CD4(+)CD25(+)) in recipient mice prior to transplant by modulating CD28/CTLA-4 expression. These induced Tregs suppressed proliferation of CD4(+)CD25(-) T cells ex vivo. TGFβ2-DCs delayed corneal allograft rejection and TGFβ2-DC recipient mice had significantly more splenic Tregs expressing Foxp3 and CTLA-4, but fewer CD28+ Tregs. Expression of GITR, CD69, and CD45RB were similar in TGFβ2-DC and control mice. Therefore, the phenotype of TGFβ2-DCs suggests they are tolerogenic DCs (tolDCs). In vivo, these cells increased the number and function of Tregs by modulating CD28/CTLA-4 expression. The suppressor Tregs induced by TGFβ2-DCs may be involved in the induction of ACAID, which helps to suppress corneal allograft rejection. Our results provide proof of principle for the use of tolDCs as immunotherapy during transplant.

Alloimmunity and Tolerance in Corneal Transplantation

“…Studies on murine models of penetrating keratoplasty have demonstrated that administration of donor-derived tolDCs to hosts prior to transplantation increases the frequencies of Foxp3 hi Tregs and significantly improves corneal allograft survival (109). Results of a recent study indicate that the beneficial effect of tolDCs on corneal graft survival is mediated through expansion of CTLA-4 expressing Tregs and downregulation of CD28 + Tregs (110). Given that tolDCs induce allotolerance primarily through Treg expansion, the majority of studies have focused on modification of Treg function to promote graft survival.…”

TGF-β2 interfering oligonucleotides used as adjuvants for microbial vaccines

“…The sTGF-2 on the B cells was reported to decrease the expression of CD69, CD40, CD80, CD86, and MHC II molecules on the B cells. 16,17 Therefore, we may presume that TIO3 could increase the expression of CD69, CD40, CD80, CD86, and MHC II molecules on the Tregs. 60,61 The data suggest that the sTGF-2 could be an inhibitory molecule to attenuate humoral immune responses to vaccines by promoting Treg generation.…”

Phenotypic Peculiarities of Dendritiс Cells Differentiated From Blood Monocytes in Patients With Kidney Cancer

“…Фенотип ДК также был охарактеризован определением экспрессии еще 3-х маркеров: CD80, CD86 и HLA-DR. CD80 (B7-1, B7 и BB1) и CD86 (B7-2, B70 и Ly-58) представляют собой гликопротеины, принадлежащие к суперсемейству иммуноглобулинов, с массой, соответственно, 60 и 80 кДа. Доказано, что взаимодействие CD80 и CD86 на ДК с CD28 обеспечивает мощный костимуляторный сигнал для активации Т-лимфоцитов, тогда как их взаимодействие с CTLA-4 обеспечивает ингибирующий сигнал для Т-клеток [9,31]. HLA-DR (антиген главного комплекса гистосовместимости II класса) является гетеродимерным гликопротеином, который экспрессируется на многих типах клеток иммунной системы, для ДК является критическим для осуществления эффективной антигенпрезентации [6,8].…”