Alloantigen specific CD8+CD28− FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity

Abstract

Endothelial cells have been shown to activate T cell responses to alloantigens, triggering transplant rejection. However, they may also play a role in tolerance induction. Using RT-PCR we show here that alloantigen specific CD8(+)CD28(-) T suppressor cells generated in vitro are FOXP3 positive and interact with human endothelial cells. This interaction results in the induction of inhibitory receptors and down-regulation of costimulatory and adhesion molecules, thus rendering endothelial cells tolerogenic. In turn, tolerized endothelial cells elicit the differentiation of CD8(+)CD28(-) FOXP3(+) T suppressor cells. Taken together our data demonstrate a functional and phenotypic overlap between tolerogenic dendritic cells and endothelial cells. Furthermore, alloantigen specific CD8(+)CD28(-) FOXP3(+) T cells, which trigger the upregulation of inhibitory receptors in endothelial cells, are present in the circulation of heart allograft recipients in quiescence as demonstrated by flow cytometry, RT-PCR and luciferase transcription assays. Their detection facilitates the identification of patients who may benefit from partial or complete cessation of immunosuppressive therapy, a goal of obvious importance given the morbidity and mortality associated with chronic immunosuppression. Modulation of endothelial cells in favor of promoting tolerance may be important for long-term survival of organ allografts.

HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells

“…Suppression may occur through direct binding of inhibitory cell surface molecules such as CTLA-4 to costimulatory molecules (including CD80 and CD86) on effector T cells (43,44). These HIV-specific suppressor CD8 ϩ T cells may also recognize MHC peptide complexes on the cell surface of APCs, triggering the up-regulation of the inhibitory receptors Iglike transcripts (ILT)3 and ILT4 and the down-regulation of costimulatory molecules rendering the APC tolerogenic (33,45,46). In addition, programmed death-1 ligation has been suggested as a suppressor mechanism of regulatory T cells resulting in decreased T cell proliferation and IL-2 production (47, 48) and may also be involved.…”

Generation and Regulation of CD8+ Regulatory T Cells

“…These cells have an IL-10 + CCR7 + CD45RO + CD8 + phenotype and can suppress tumor antigen-specific T cell effector function through IL-10 secretion (16). Similarly, immature conventional DC can induce CD8 + Treg (17) and FoxP3 + alloantigen-specific CD8 + CD28 -T suppressor cells can also be generated in vitro by tolerized endothelial cells (18). Primary suppressive CCR7 + CD45RO + CD8 + T cells have been isolated from human tumors, suggesting that they may contribute to the tumor-induced immunosuppressive network (19).…”

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…Certain surface phenotypes such as CD28 À [7], CD122 1 [8], CD8aa 1 [9,10], latencyassociated peptide (LAP) 1 [11] and restriction to the nonclassical MHCI molecule Qa-1 [12] have been linked with immunosuppressive functions of CD8 1 T cells. However, Foxp3 expression was either absent in these populations [8,9,[13][14][15], incongruent with the defining surface phenotype [11] or was not investigated specifically on a protein level [16]. Additionally, the isolation of viable CD8 1 Foxp3 1 populations was hampered by the nuclear localization of Foxp3 in conjunction with the occurrence of these cells at low numbers in nonmanipulated mice [2,17], rendering the identity and relevance of mouse CD8 1 Foxp3 1 T cells unclear.…”

“…with the defining surface phenotype [11] or was not investigated specifically on a protein level [16]. Additionally, the isolation of viable CD8 1 Foxp3 1 populations was hampered by the nuclear localization of Foxp3 in conjunction with the occurrence of these cells at low numbers in nonmanipulated mice [2,17], rendering the identity and relevance of mouse CD8 1 Foxp3 1 T cells unclear.…”