In Vivo Environment Necessary to Support Transplanted Donor Mouse T Regulatory Cells

Abstract

CD4þ Foxp3 þ T regulatory cells (T regs ) are essential for maintaining immunological tolerance, which could be harnessed for novel cell-based therapies to prevent allograft rejection and control autoimmunity. However, the use of T regs for therapy is hindered by the inability to generate sufficient cell numbers to inhibit desired immune response(s) and achieve stable engraftment of the donor-T reg cell inoculums. The present study was undertaken to investigate the in vivo requirements to promote engraftment of adoptively transferred T regs and induce tolerance. We established that not only is peripheral space required, but competition from endogenous T regs must be minimized for successful donor-T reg engraftment with IL-2 critical for driving their proliferation and survival. Moreover, these studies revealed a critical level of donor-T reg engraftment was required for tolerance induction to skin transplants. These mouse studies lay the foundation for development of novel T reg approaches for tolerance induction in the clinic involving not only organ or cellular transplantation, but also to re-establish self-tolerance in autoimmune settings.

Adoptive T Regulatory Cell Therapy for Tolerance Induction

“…This critical requirement was confirmed in common laboratory mouse strains in absence of genetic manipulations, specifically in studies of BM conditioning in non-autoimmune C57BL/6 and Balb/c strains (75). Infused T regs engrafted, persisted long-term, and contributed to tolerance induction to skin allografts.…”

“…However, the loss of T reg phenotype was dampened when T regs were co-injected with CD4 + GFP-negative cells and Foxp3 loss emerges in absence of IL-2 (76). Despite initial lymphopenia induced by our BM conditioning, donor-positive CD4 T-cells maintain Foxp3 expression in both mouse strains (75). These data together with immune-compromised strains revealed the importance of available “space” within the T reg niche and minimizing competition at the time of T reg infusion for long-term donor T reg persistence.…”

“…However, residual T reg compartment following ablation was also highly dependent on IL-2 and IL-7 acted more as a survival factor (100). Moreover, IL-2 was also critical for the growth and survival of infused T regs following conditioning (75). Despite low IL-2 in conditioned mice, levels are sufficient to drive substantial proliferation T reg compartment.…”

The Induction and Maintenance of Transplant Tolerance Engages Both Regulatory and Anergic CD4+ T cells

“…This does not, of course, rule out a role for Foxp3 + T-cells in tolerance maintenance, as the level of their activity may, through homeostatic mechanisms, have been adjusted to that corresponding to residual effector function in the treated hosts (29, 30). These finding may be of importance for the implementation of Treg cell therapy in organ transplantation (31).…”

Engineering Biomimetic Materials for Islet Transplantation

“…While the use of ex vivo expanded Tregs has potential, ensuring stable engraftment of these cells is an appreciable challenge, as substantial Treg loss is commonly observed following transplantation [68]. The generation of Tregs at the site of implantation may be a more stable approach, whereby T cell recruited to the islet graft can be converted to Tregs by the local microenvironment.…”