Tbet is a critical modulator of FoxP3 expression in autoimmune graft- versus -host disease

Abstract

CD4+ T-helper subsets drive autoimmune chronic graft-versus-host disease, a major complication after allogeneic bone marrow transplantation. However, it remains unclear how specific T-helper subsets contribute to chronic graft-versus-host disease. T-helper type 1 cells are one of the major disease-mediating T-cell subsets and require interferon-γ signaling and Tbet expression for their function. Regulatory T cells on the other hand can inhibit T-helper type 1 cell-mediated responses. Using an established murine model that isolates the autoimmune component of graft-versus-host disease, we hypothesized that T-helper type 1 cells would restrict FoxP3-driven regulatory T cells. Upon transfer into immune-deficient syngeneic hosts, alloreactive Tbx21−/−CD4+ T cells led to marked increases in FoxP3+ cells and reduced clinical evidence of autoimmunity. To evaluate whether peripheral induction contributed to regulatory T-cell predominance, we adoptively transferred Tbx21−/− T cells that consisted of fate mapping for FoxP3: recipients of flow-purified effector cells that were Foxp3− and Tbx21−/− had enhanced T-regulatory-cell predominance during autoimmune graft-versus-host disease. These data directly demonstrated that peripheral T-regulatory-cell induction was inhibited by Tbet. Finally, Tbx21−/− T-regulatory cells cross-regulated autoimmune wild-type T-effector-cell cytokine production in vivo. The Tbet pathway therefore directly impairs T-regulatory-cell reconstitution and is consequently a feasible target in efforts to prevent autoimmune graft-versus-host disease.

T helper 2 differentiation is necessary for development of lymphedema

“…Female WT (C57BL/6J; #000664), CD4KO [CBY.129S2 (B6)-Cd4 tm1mak /J; #002663], T-betKO (B6.129S6-Tbx21 tm1Glm /J, #004648), and STAT6KO (B6.129S2(C)-Stat6 tm1Gru /J; #005977) mice were purchased from The Jackson Laboratory (Bar Harbor, Maine) and maintained in a pathogen-free, temperature-and light-controlled environment and fed ad libitum. CD4KO, T-betKO, and STAT6KO mice have previously been established as models for CD4 + T cell, Th1 cell, and Th2 cell deficiency, respectively, and were therefore chosen for this study to determine the effect of these particular cell types on the development of lymphedema following lymphatic injury [15,17,21]. A minimum of 5 mice were used for each experimental group and assays were performed in triplicate.…”

“…Early commitment to the Th1 lineage is induced by the activation of STAT1, which then promotes T-bet expression, which in turn results in the production of IL-12Rβ2 and interferon gamma (IFN-γ). As such, the absence of T-bet results in a deficiency of Th1 cells and, ultimately, the failure to activate antimicrobial mechanisms against a variety of pathogens [13,15]. This has been demonstrated by Finotto et al, who showed that mice possessing a targeted mutation for T-bet have markedly reduced IFN-γ levels and dysfunctional immune responses [14].…”

Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT

“…These results suggest that T-bet is important for migration and cytokine production during GVHD and GVT. Loss of T-bet in donor T cells in a model of chronic GVHD and autoimmunity led to an increase in Foxp3+ Tregs and reduced clinical signs after allotransplantation ( 59 ). Dual TCR T cells, which are increased in chronic GVHD (cGVHD), express T-bet, suggesting a role for T-bet even in cGVHD alloresponses ( 60 ).…”