Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MKActivation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19: 345-354
Forkhead box P3 (FOXP3) is currently thought to be the most specific marker for naturally occurring CD4(+)CD25(+) T regulatory cells (nTregs). In mice, expression of FoxP3 is strictly correlated with regulatory activity, whereas increasing evidence suggests that in humans, activated T effector cells (Teffs) may also express FOXP3. In order to better define the role of FOXP3 in human Teff cells, we investigated the intensity and kinetics of expression in ex vivo Teff cells, suppressed Teff cells and Teff cell lines. We found that all dividing Teff cells expressed FOXP3, but only transiently, and at levels that were significantly lower than those in suppressive nTregs. This temporary expression in Teff cells was insufficient to suppress expression of reported targets of FOXP3 repressor activity, including CD127, IL-2 and IFN-gamma, and was not correlated with induction of a nTreg phenotype. Thus expression of FOXP3 is a normal consequence of CD4(+) T cell activation and, in humans, it can no longer be used as an exclusive marker of nTregs. These data indicate that our current understanding of how FOXP3 contributes to immune tolerance in humans needs to be re-evaluated.
"Although FOXP3 has been considered as a lineage-specifying master regulator of Treg functions , several indications that FOXP3 expression per se might not be sufficient to stably maintain Treg suppressive function or reliably delineate functional Tregs. For example, activated human effector T cells can transiently express FOXP3 at a low level without acquiring suppressive activity . Also, human peripheral blood CD4+ T cells contain a FOXP3+ T cell subpopulation that does not exhibit suppressive activity and even produces proinflammatory cytokines upon activation . "
[Show abstract][Hide abstract] ABSTRACT: The emergence of regulatory T cells (Tregs) as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4+CD25highCD127low regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4+CD25highCD127low regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX-40. Also, 1,25(OH)2D3 and TX527 treatment inhibit the production of effector cytokines IFN-γ, IL-9, and IL-17. Importantly, 1,25(OH)2D3 and TX527 promote the induction of IL-10-producing CD4+CD25highCD127low T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes.
PLoS ONE 10/2014; 9(10):e109194. DOI:10.1371/journal.pone.0109194 · 3.23 Impact Factor
"This expansion however would not be sufficient to control cell activation induced by the HTLV-1 infection. However, it has been reported that Forkhead box P3 (FOXP3) protein may be transiently expressed on activated T CD4+ cells and its expression does not necessarily convey regulatory function [40, 41]. In the present study, we were unable to evaluate the function of these cells. "
[Show abstract][Hide abstract] ABSTRACT: Background:
High HTLV-1 proviral load (PVL) is mainly found in infected individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However one third of asymptomatic carriers may have high PVL. This study aimed to evaluate the impact of PVL in the activation of T lymphocytes of asymptomatic individuals infected with HTLV-1.
Membrane activation markers (CD25+, CD28+, CD45RO+, CD69+, CD62L+, HLA-DR+), FoxP3+ and intracellular IFN-γ expression were evaluated on both CD4+ and CD8+ T-lymphocytes from asymptomatic carriers with PVL ≥ and < 1% of infected cells, using flow cytometry. HTLV-1 proviral load was determined using real-time PCR.
Asymptomatic carriers with PVL ≥ 1% presented a higher frequency of CD4+CD25+CD45RO+ (13.2% vs. 4%, p = 0.02), CD4+HLA-DR+ (18% vs. 8.3%, p = 0.01) and CD4+IFN-γ+ (4.5%; 1%, p = 0.01) T-cells, than healthy donors. HTLV-1 PVL was directly correlated with the proportion of CD4+CD25+CD45RO+ T-cells (R = 0.7, p = 0.003). Moreover, a significant increase in the proportion of CD4 + FoxP3+ T-cells was observed in HTLV-1-infected individuals, compared to healthy donors.
HTLV-1 PVL is associated with activation of both CD4+ and CD8+ T-lymphocytes in asymptomatic individuals. Prospective studies should be conducted to evaluate whether asymptomatic individuals with higher PVL and high immune activation are more prone to developing HTLV-1-associated diseases.
"In certain conditions, both murine and human naïve CD4+ T cells transiently express Foxp3, without acquiring a suppressive function [39–41]. Moreover, natural Tregs from the thymus have been shown to convert to effector/helper T cells with a decrease of Foxp3 expression . "
[Show abstract][Hide abstract] ABSTRACT: Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3(+) T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity.
Research Journal of Immunology 07/2014; 2014:943149. DOI:10.1155/2014/943149
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