The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation

Abstract

Regulatory T cells (Tregs) prevent graftversus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by IntroductionNaturally arising CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells (Tregs) are a major regulator of adaptive immunity. 1 Depletion of Tregs enhances microbial and tumor immunity, 2,3 while their adoptive transfer protects animals from autoimmune diseases, 1,4,5 induces tolerance following organ transplantation, 5 and prevents graftversus-host disease (GvHD) following hematopoietic cell transplantation (HCT). 6-8 Given these observations, immunotherapy with Tregs is being explored for clinical applications. 9 However, the impact of Treg transfer on short-and long-term host immunity remains not well understood.In HCT, GvHD damages the stroma of the thymus and secondary lymphoid organs, thereby decreasing thymic output, impairing peripheral expansion of T cells, [10][11][12][13][14][15] and consequently leading to a prolonged immunodeficiency state. 11,16 Given the pathophysiologic link between GvHD and immune reconstitution, protection from GvHD by Tregs would potentially promote timely and complete immune recovery. However, quantitative immune reconstitution does not necessarily translate into recovery of cellular function, 17 and the long-term persistence of transferred Tregs in vivo 18 may diminish or abrogate functional effector responses.Tregs suppress the priming, expansion, and/or function of conventional T cells (Tcons). [19][20][21] However, it is unclear whether this regulation is antigen specific. Following HCT, specific suppression of alloreactive T cells is beneficial, as donor T cells have dual and opposing roles of mounting antitumor and antimicrobial responses and inducing GvHD. Observations from autoimmune disease models that Tregs can induce bystander suppression 5,22,23 and infectious tolerance 24,25 suggest nonspecific inhibition following their activation. Given the multiorgan involvement of GvHD, we anticipate broader nonspecific suppression by polyclonal donor Tregs. Thus, we hypothesized that the adoptive transfer of Tregs would attenuate GvHD via nonspecific suppression of effector responses, which could in turn compromise viral and tumor immunity following HCT.The aims of our studies were to determine if Tregs affect the generation and expansion of thymic-derived naive donor T cells and mature CD4 ϩ and CD8 ϩ T cells transplanted with the allograft, and if effective immune responses can be generated in the presence of Tregs. Our results demonstrate that Tregs prevent damage of the thymus and peripheral lymphoid tissues associated with GvHD. Protection of both central and peripheral lymphoid compartments by Tregs in turn facilitates the development and expansion of an enhanced T-cell repertoire that results in improved reconstitution of functional immune responses following HCT. Meth...

Umbilical cord blood graft engineering: challenges and opportunities

“…62,63 Although there is concern that Treg infusion post-transplant may potentially impair immune reconstitution, Tregs may suppress alloreactive T-cells, whereas actually facilitating functional immune reconstitution through inhibition of GvHDinduced thymic and secondary lymphoid microenvironmental damage. [64][65][66][67] Immune function is preserved in murine models of Treg infusion, suggesting that the suppression of GvHD is relatively specific. 68 Another theoretical concern with adoptive transfer of Tregs is the potential for impairment of GVL effect with increased risk of disease relapse.…”

New perspectives on the biology of acute GVHD

“…[81][82][83][84][85][86] Furthermore, viral immunity is preserved in the presence of Tregs after allogeneic HCT. 87 The mechanisms for suppression in the context of GVHD remain completely unknown. None- …”

Allogeneic intra-BM-BMT plus adult thymus transplantation from same donor has benefits for long-term survival even after sublethal irradiation or low-dose BM cell injection

“…The low number of all lymphocyte subsets in the mice treated with IBM-BMT plus DLI may be the result of the GVHD. 22 From the above results, there is a clear correlation between the involvement of mature T cells in transplanted cells and donor chimerism, suggesting that the alloresponse of the T cells plays an important role in reconstituting the recipients with donor cells. However, severe GVHD was not evident in the mice treated with IBM-BMT plus ATT.…”