Shiqiao Luo

In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells

Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis. Therefore, we designed this study to test the hypothesis that human regulatory T cells (Treg cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of Treg cells, sorted via two separate strategies, to prevent transplant arteriosclerosis in a clinically relevant chimeric humanized mouse system. We found that the in vivo development of transplant arteriosclerosis in human arteries was prevented by treatment of ex vivo–expanded human Treg cells. Additionally, we show that Treg cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional Treg cells. Our results demonstrate that human Treg cells can inhibit transplant arteriosclerosis by impairing effector function and graft infiltration. We anticipate our findings to serve as a foundation for the clinical development of therapeutics targeting transplant arteriosclerosis in both allograft transplantation and other immune-mediated causes of vasculopathy.

Location and Time-Dependent Control of Rejection by Regulatory T Cells Culminates in a Failure to Generate Memory T Cells

Adaptive CD25+CD4+ regulatory T cells (Treg) can be induced following exposure to alloantigen and may function alongside naturally occurring Treg to suppress allograft rejection when present in sufficient numbers. However, the location of the Treg as they function in vivo and the mechanisms used to control donor-reactive T cells remains ill-defined. In this study, we used a CD8+ TCR transgenic model of skin allograft rejection to characterize in vivo activity of donor-reactive Treg cells during induction of transplantation tolerance. We demonstrate that, initially after skin transplantation, Treg attenuate the priming of donor-reactive naive CD8+ T cells in the lymphoid tissue draining the graft site. However, with time, peripheral suppression is overcome despite the continued presence of Treg, resulting in the priming of donor-reactive CD8+ T cells and graft infiltration by the resultant effector T cells and induction of a “Tc1-like” intragraft gene expression profile. These intragraft effector CD8+ T cells are then prevented from eliciting rejection by Treg that simultaneously infiltrate the skin allografts, resulting in a failure to generate donor-reactive memory CD8+ T cells. Overall, these data demonstrate for the first time that donor-reactive Treg can suppress allograft rejection using distinct mechanisms at different sites in vivo with the overall outcome of preventing the generation of donor-reactive memory T cells.

Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help

There is now considerable evidence suggesting that CD8+ T cells are able to generate effector but not functional memory T cells following pathogenic infections in the absence of CD4+ T cells. We show that following transplantation of allogeneic skin, in the absence of CD4+ T cells, CD8+ T cells become activated, proliferate, and expand exclusively in the draining lymph nodes and are able to infiltrate and reject skin allografts. CD44+CD8+ T cells isolated 100 days after transplantation rapidly produce IFN-γ following restimulation with alloantigen in vitro. In vivo CD44+CD8+ T cells rejected donor-type skin allografts more rapidly than naive CD8+ T cells demonstrating the ability of these putative memory T cells to mount an effective recall response in vivo. These data form the first direct demonstration that CD8+ T cells are able to generate memory as well as effector cells in response to alloantigen during rejection in the complete absence of CD4+ T cells. These data have important implications for the design of therapies to combat rejection and serve to reinforce the view that CD8+ T cell responses to allografts require manipulation in addition to CD4+ T cell responses to completely prevent the rejection of foreign organ transplants.

Regulatory T cells: Potential in organ transplantation

Active regulation or suppression of donor reactive cells is emerging as a key mechanism for inducing and maintaining unresponsiveness to donor alloantigens. Accumulating evidence suggests that a balance between immunoregulation and deletion of donor alloantigen reactive T cells can provide effective control of immune responsiveness after organ or cell transplantation. In many settings, immunoregulatory activity is enriched in CD4+ T cells that express high levels of CD25, and common mechanisms appear to be responsible for the activity of regulatory T cells in both transplantation and the control of reactivity to self-antigens.

Functional dichotomy of NK cells in organ transplantation

Evaluation of: Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J. Exp. Med. 203, 1851–1858 (2006). Natural killer (NK) cells have the potential to display different functional activities after transplantation. The traditional view is that NK cells have the capacity to contribute to rejection by facilitating the activation/differentiation of leukocytes that destroy the graft. By contrast, in the article under review, a novel role for NK cells was identified in the setting of costimulation blockade where alloreactive NK cells of recipient origin were found to have the capacity to kill donor-derived antigen-presenting cells, thereby reducing T-cell priming and promoting long-term skin graft acceptance.