Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD

Abstract

CD4 ؉ CD25 ؉ regulatory T cells (Tregs) control immune responses to self-and foreign antigens and play a pivotal role in autoimmune diseases, infectious and noninfectious inflammation, and graft rejection. Since recent experimental studies have indicated that Tregs were able to ameliorate graft-versus-host disease (GvHD), we analyzed the number of infiltrating Tregs in the intestinal mucosa as one site of GvH reactivity using immunoenzymatic labeling to enumerate IntroductionDespite the prophylactic use of potent immunosuppressants, severe graft-versus-host disease (GvHD) is-besides infections-the most relevant complication after allogeneic stem cell transplantation. Immunologically, acute GvHD is characterized by an expansion of donor lymphocytes with cytotoxic reactivity against recipient histocompatibility antigens. The resulting clinical picture includes life-threatening destruction of skin, gut, and liver tissue.In acute GvHD, the transferred immune system lacks the capability to gain control over alloreactive T-cell clones. Therefore, the understanding of mechanisms by which an organism controls allo-or autoimmune reactivity is crucial for the development of successful strategies to prevent and/or control GvHD. Recently, these mechanisms have been further elucidated by the description of a distinct CD4 ϩ T-cell population with the capability to confer nonresponsiveness to T cells against autologous and allogeneic antigens. [1][2][3] These suppressor or regulatory T cells were originally described as a lymphocyte subset that prevents autoimmunity caused by neonatal thymectomy in mice 1 and are characterized by the expression of the interleukin-2 (IL-2) receptor ␣-chain (CD25). More recently, FOXP3, which encodes for a forkhead/winged helix transcription factor called Scurfin, has been identified to be a key regulatory gene required for the development and functional activity of regulatory T cells. [4][5][6][7] Tregs are able to suppress CD4 ϩ and CD8 ϩ T-cell responses to auto-and alloantigens in a contactdependent fashion. 8 In animal models, they can prevent graft rejection 2,3,9 and autoimmune diseases, 8,10 and there is also evidence that inappropriate numbers of Tregs may contribute to the development of chronic inflammatory diseases. 11 Consequently, the question has been raised whether Tregs are also capable of suppressing GvHD. Indeed, it has been shown in different murine models that freshly isolated or ex vivo-expanded donor-type CD4 ϩ CD25 ϩ Tregs are able to delay or even prevent GvH reactivity. [12][13][14][15] Consistent with this, the selective depletion of Tregs leads to an increased severity of acute GvHD in vivo. 16 In humans, however, available data are ambiguous. Whereas Clark et al found elevated numbers of CD4 ϩ CD25 high cells in the peripheral blood of patients with chronic GvHD, 17 Miura et al observed a significantly decreased FOXP3 mRNA expression in the peripheral blood of patients suffering from allogeneic or autologous GvHD. 18 Since the presence of Tregs in the peripheral blo...

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

“…39,41 Decreased FoxP3 levels have been associated with GVHD in several studies. 31,[42][43][44] Expression of Foxp3 negatively correlated with the severity of GVHD in patients, but positively correlated with recent thymic emigrants. These findings substantiate that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms following transplantation.…”

Immune modulation and chronic graft-versus-host disease

“…[29][30][31] In several series, including our own, Treg number as measured by CD4 þ CD25 þ FoxP3 þ staining was diminished in patients with cGVHD. [32][33][34] Moreover, Treg number returned to normal in patients with resolved cGVHD. However, there have been conflicting data on Treg number and cGVHD.…”

Treatment with bortezomib of human CD4+ T cells preserves natural regulatory T cells and allows the emergence of a distinct suppressor T-cell population

“…18 This property turns bortezomib into a potential therapeutic tool against GVHD, raising the possibility of in vitro purging alloreactive T cells while preserving effector T cells with other specificities. Due to the suggested importance of nTreg cells in the control of GVHD, [19][20][21][22] in the current manuscript we have analyzed the effect of bortezomib on nTreg-cell viability. Our results demonstrate that the addition of bortezomib to activated CD4 + T-cell cultures allows survival of nTreg cells and, moreover, promotes the emergence of a distinct suppressor CD4 + T-cell population (bTreg) that strongly inhibits the activation of in vitro stimulated T cells.…”