Efficient Therapeutic Function and Mechanisms of Human Polyclonal CD8CD103Foxp3 Regulatory T Cells on Collagen-Induced Arthritis in Mice.

Objective: To investigate the potential therapeutic effect in a rheumatoid arthritis model of stable human CD8 regulatory T cells (hCD8Tregs) induced by TGF-1 and rapamycin (RAPA) .

Methods: Human CD8T cells were isolated from human peripheral blood mononuclear cells and induced/expanded with TGF-1 and RAPA along with anti-CD3/28 beads and IL-2 and harvested as hCD8Tregs. The phenotypes, suppressive characteristics, and stability of the hCD8Tregs in an inflammatory microenvironment were examined . Human CD8Tregs were transfused into an acollagen-induced arthritis (CIA) mouse model, and their therapeutic effects and related mechanisms were investigated.

Results: Human CD8Tregs induced by TGF-1/RAPA showed high expression of Foxp3 and CD103, exhibited vigorous suppression ability, and were stable in inflammatory microenvironments. In CIA mice, the clinical scores, levels of anti-collagen IgG antibody, and cartilage destruction were significantly reduced after adoptive transfusion with hCD8Tregs. Moreover, hCD8Treg treatment significantly reduced the number of Th17 cells, increased the number of CD4IFN- T cells, and produced self CD4Foxp3Tregs . In an cell coculture assay, hCD8Tregs significantly inhibited mouse CD4 effector T cell proliferation, induced mouse CD4Foxp3Treg and CD4IFN- Th1 cell production, reduced Th17 cell development, and downregulated CD80/86 expression on mature DCs (mDCs).

Conclusion: TGF-1/RAPA can induce hCD8Tregs with stable suppressive characteristics, which could significantly alleviate the severity of CIA based on their stable suppressive ability in an inflammatory microenvironment and further influence the function of other downstream cell subtypes. Human CD8Tregs might be a therapeutic strategy for rheumatoid arthritis.