Expansion of a restricted residual host T reg-cell repertoire is dependent on IL-2 following experimental autologous hematopoietic stem transplantation.

We previously identified a population of residual T(reg) cells following autologous hematopoietic stem transplantation (HSCT), that rapidly undergoes significant expansion in lymphopenic transplant recipients prior to repopulation by donor de novo derived T(reg) cells. These CD4(+) Foxp3(+) T cells provide protection from the development of autoimmune disease. Although ablative conditioning results in excess IL-7 and IL-15, IL-2 is typically not found at high levels following autologous HSCT. We therefore examined the role of these three STAT-5 signaling cytokines in the expansion of residual T(reg) cells after autologous HSCT. The present study found that the residual T(reg) cell population included surviving peripheral host Foxp3(+) CD4(+) T cells whose expansion was critically dependent on IL-2, which could be solely provided by surviving host cells. IL-7 was found to contribute to T(reg) cell homeostasis, however, not as a growth factor but rather for their persistence. In conjunction with this expansion, TCR spectratype analyses revealed that the residual host T(reg) -cell compartment differed from that present in non-conditioned healthy mice since the residual host Treg cells exhibit a limited TCR diversity. Collectively, these data indicate that the proliferation of T(reg) and T effector (T(eff) ) cells post-HSCT utilize separate pools of cytokines which has important implications regarding the development of clinical strategies to elicit the desired immune responses in patients post-transplant.

Targeting Treg cells in situ: emerging expansion strategies for (CD4(+)CD25(+)) regulatory T cells.

Recognition of the ability of CD4(+)FoxP3(+) T cells (Treg) to influence the generation of peripheral immune responses has engendered enthusiasm for the development of strategies utilizing these cells to regulate immune responses in clinically important settings including transplantation, autoimmunity and cancer. A number of studies have reported effective regulation utilizing ex-vivo expansion approaches and subsequent transfer of Treg populations in experimental models. This commentary discusses recently emerging strategies to activate and expand Treg cells in situ which include antibodies, antigen presenting cells and the use of IL2 / anti-IL2 antibody complex. The development of reagents which can stimulate and / or remove Treg cells in situ would represent an important advance towards facilitating new opportunities to harness this compartment for the augmentation of 'wanted' or suppression of 'unwanted' immune responses. Simultaneous targeting of multiple molecules on Treg cells may ultimately enable more effective control of this regulatory sector.

Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT.

Reconstitution of the recipient lymphoid compartment following hematopoietic cell transplantation (HCT) is typically delayed. The present studies investigated the residual host CD4(+)CD25(+)Foxp3(+) (Treg) compartment after several conditioning regimens, including T cell-depleted and T cell-replete HCT and observed (1) a small number of recipient Treg cells survived aggressive conditioning; (2) the surviving, that is, residual Tregs underwent marked expansion; and (3) recipient CD4(+)FoxP3(+) cells composed the majority of the Treg compartment for several months post-syngeneic HCT. Notably, residual Tregs also dominated the compartment post-HCT with T cell-depleted (TCD) major histocompatibility complex-matched allogeneic bone marrow but not following T cell-replete transplantations. The residual Treg cell compartment was functionally competent as assessed by in vitro lymphoid suppression and in vivo autoimmune disease transfer assay. These observations support the notion that functional host Tregs initially occupy a niche in lymphopenic transplantation recipients, undergo significant expansion, and contribute to the compartment for an extended period before donor-derived CD4(+)FoxP3(+) T cells eventually compose the majority of the compartment. In total, the findings suggest that the presence of host Tregs may be important to consider regarding elicitation of immune (eg, antitumor, vaccine) responses in recipients during the early post-transplant period involving autologous and certain allogeneic HCT regimens.