Comparative analysis of the therapeutic potential of two inducible Treg cell populations in experimental model of arthritis

Backgroundand objectives Adoptive cell transfer of T regulatory (Treg) cells is a promising approach to restore tolerance in autoimmune disease. However the various type of Tregs, their doses of injection and their in vivo-suppressive mechanism need to be precisely define to clearly establish which Tregs will be able to dampen efficiently the immune response in the various settings. In this study, the authors compared the therapeutic potential of two IL10-secreting Tregs: Tr1 and CD49b-induced Tregs. The authors previously demonstrated that a single injection of iDC-induced CD49b T cells reversed clinical symptoms of arthritis. This inducible CD49b Treg population shares several phenotypic markers as well as immunosuppressive properties compared with the in vitro-expanded IL-10-secreting Tr1 cells. More recently, the authors provide evidence that injections of Tr1 cells, after the onset of the disease, could protect mice from severe arthritis. In the present study the authors perform adoptive cell transfer experiments of these two inducible Treg cells in order to compare their impact on the immune response. Materials and methods CD49b Treg cells were generated in naive mice following repetitive injections of iDC. The purification was based on the negative selection of CD4 T cells isolated from the spleen and liver of the iDC-vaccinated mice. Cell sorting experiments were realised to obtain 98% pure CD49b T cells. Collagen type II (bCII) specific Tr1 clones were obtained from TCR transgenic mice and expanded in vitro. Selected clones showed in vitro antigen specificity, Tr1 cytokine profile and IL10- and tumour necrosis factor β-dependent suppressive activity. Results Several doses of CD49b or Tr1 cells were injected intravenously at day 28 in established collagen-induced arthritis. Clinical signs of arthritis were scored, as well as biological parameters such as the level of anti-bCII antibodies in sera and the cytokine profile of bCII specific T cells. The authors defined for both Treg cell populations the dose effect in curative settings experiments. One single dose of 3×106 or 1×106 of Tr1 cell administration could reduce the incidence and severity of CIA. Interestingly, higher dose of 10M of Tr1 cells did not improve the disease. In the same manner, the dose of 105 CD4CD49b + cells reverse clinical symptom with a lack of efficacy of higher doses. The homing ability and plasticity of Tr1 cells was also investigated. Conclusions These results suggest that even if the Treg cells present some similarities, one should precisely define the dose and type of Treg that will be efficient in each experimental setting.