Treg Cell Plasticity Research Articles

Human retrovirus promotes the plasticity of regulatory T cells into T helper type 1-like cells through the T-bet transcriptional activation in neuroinflammatory disease

Recently, it has become increasingly clear that some committed effecter and regulatory T (Treg) cells are not stable, and the plasticity of these T-cells may be related to the pathogenesis of autoimmunity and inflammatory diseases [1]. However, the precise mechanisms that allow for T cell plasticity have not yet been clearly understood. Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is associated with multiorgan inflammatorydisorders such as HTLV-1- associated myelopathy (HAM/TSP), HTLV-1- associated arthropathy (HAAP), uveitis, Sjogren syndrome, and polymyositis [2-5]. HTLV-1-infected T cells may contribute to development of these disorders, since the number of HTLV-1-infected T cells circulating in the peripheral blood is higher in patients [6]. HTLV-1 mainly infects CD4+ T helper (Th) cells that play central roles in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells differentiated from naive CD4+ T-cells are classified into 4 major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. We recently demonstrated that CD4+CD25+CCR4+ T cells, which mainly include suppressive T-cell subsets such as Treg and Th2 under healthy conditions, are the predominant viral reservoir of HTLV-1 in both adult T-cell leukemia/lymphoma (ATL) and HAM/TSP [7]. Interestingly, T-cells of this subset become Th1-like cells with overproduction of IFN-γ in HAM/TSP, suggesting that HTLV-1 may intracellularly induce Tcell plasticity from Treg to IFN-γ+ T cells [7].In this study, using human T-cell line and HTLV-1 infected CD4+CD25+CCR4+ T-cells of HAM/TSP patients, the virus-encoded transactivating HTLV-1 Tax protein was demonstrated to induce the IFN-γ production through the expression of T-box 21(Tbx21)/T-bet, a transcription factor that is known to direct the differentiation of naive CD4+ cells into IFN-γ-expressing Th1 cell. HTLV-1 Tax was also demonstrated to enhance promoter activity of Tbx21/T-bet cooperatively with transcription factor Specificity Protein 1 (Sp1). Furthermore, transfer of HTLV-1 tax gene in CD4+CD25+CCR4+ T-cells using a lentiviral vector resulted in the loss of regulatory function of these T cells. This is the first report to our knowledge demonstrating the role of a specific viral product (HTLV-1 Tax) on the expression of genes associated with T-cell differentiation resulting in plasticity of Treg cells into Th1-like cells. These results suggest that HTLV-1 infection-induced immune dysregulation may play an important role in the development and pathogenesis of HTLV-associated immunological diseasesthrough its interference in the equilibrium maintained among host immune responses.

Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability

Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability

STAT3 Promotes Both Natural and Inducible T Regulatory Cell Plasticity During Murine Acute GVHD

Adoptive cell transfer of FoxP3+ regulatory T cells (Tregs) has been proposed as a novel therapy for prevention of acute GVHD. Such therapy may theoretically be limited by conversion of Tregs into pathological effector T cells due to STAT3-activating inflammatory cytokines, including IL-6, IL-21, and IL-23. To better understand the role of STAT3 in Treg cell plasticity during acute GVHD, we used a B6 ⇒ BALB/c transplantation model. Donor cell populations were obtained from either, STAT3 fl/fl Foxp3-GFP (WT) or CD4-Cre, STAT3 fl/fl-Foxp3 GFP (KO). Transfer of T cell-replete, WT inocula uniformly resulted in lethality by day 14 post-BMT; in contrast, T cell-replete, STAT3-KO recipients had 100% post-BMT survival (p < 0.001). Relative to WT recipients, STAT3-KO recipients also had less GVHD by histology assessment (p < 0.05) and had increased numbers of splenic FoxP3+ T cells post-BMT (p = 0.005); in contrast, WT recipients had increased IL-17 and IFN-γ secreting T cells post-BMT (each, p < 0.01). The increased number of post-BMT FoxP3+ cells in STAT3-KO recipients may have been due to: (1) increase in “induced” Tregs from the naïve T cell pool; and (2) decrease in loss of “natural” (n)Tregs. Purified, naïve, FoxP3 negative T cells from WT or STAT3KO donors were transferred to evaluate the first possibility: after allogeneic BMT, FoxP3 induction was greatly increased in STAT3-KO recipients relative to WT recipients (p < 0.01). And, to address the second possibility, purified WT and STAT3-KO FoxP3+ Tregs were co-infused with conventional donor T cells: relative to recipients of WT nTregs, recipients of STAT3-KO nTregs had greatly increased post-BMT numbers of FoxP3 post-BMT (p < 0.05). As such, the in vivo pool of Treg cells after allogeneic BMT is controlled to a great extent by STAT3 signaling, which influences both natural and induced Treg pathways.

Regulatory T Cells: Context Matters

Regulatory T cells are important for ensuring that the immune system does not attack self and does not overreact to external antigens. Understanding how these cells develop and maintain stable function provides general insights into cellular differentiation in general, as well as new opportunities for therapeutic manipulation.