Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors

Colbeck, Emily J.; Hindley, James P.; Smart, Kathryn; Jones, Emma; Bloom, Anja; Bridgeman, Hayley; McPherson, Rhoanne C.; Turner, Darryl; Ladell, Kristin; Price, David A.; O’Connor, Richard A.; Anderton, Stephen M.; Godkin, Andrew; Gallimore, Awen

doi:10.18632/oncotarget.5584

Cited by 12 publications

(14 citation statements)

References 37 publications

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“…Although the stability of T-bet + Treg cells suggested a particular function presumably imparted by T-bet itself, we found that 12 wk-old Foxp3 YFP-Cre Tbx21 FL/FL mice were clinically indistinguishable from littermate controls, consistent with previous studies 7, 12, 13 . Foxp3 YFP-Cre Tbx21 FL/FL mice did exhibit mild T H 1 (but not CD8 T cell) activation, indicating that T-bet expression in Treg cells moderately potentiated suppression of T H 1 autoimmunity (Extended Data Fig.…”

supporting

confidence: 92%

Stability and function of regulatory T cells expressing the transcription factor T-bet

Levine

Medoza

Hemmers

et al. 2017

Nature

292

270

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Adaptive immune responses are tailored to different types of pathogens through differentiation of naïve CD4 T cells into functionally distinct subsets of effector T cells (TH1, TH2, and TH17) defined by expression of key transcription factors (TFs)1. Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked TF Foxp32, 3. Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell TFs, which have been suggested to endow Treg cells with enhanced suppressive capacity4, 5, 6. Whether expression of these factors in Treg cells—akin to effector T cells—is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here, we demonstrate that in Treg cells expression of the TH1-associated TF T-bet, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss-of-function or elimination of T-bet-expressing Treg cells—but not of T-bet in Treg cells—resulted in severe TH1 autoimmunity. Conversely, following depletion of T-bet-negative Treg cells, remaining T-bet+ cells specifically inhibited TH1 and CD8 T cell activation in agreement with their co-localization with T-bet+ effector T cells. These results suggest an essential immunosuppressive function for T-bet+ Treg cells and indicate that Treg cell functional heterogeneity is a critical feature of immune tolerance.

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supporting

confidence: 92%

Stability and function of regulatory T cells expressing the transcription factor T-bet

Levine

Medoza

Hemmers

et al. 2017

Nature

292

270

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“…T cells also enter via aberrantly formed blood and lymphatic vessels (47). It is thought that Tregs become enriched within the TIL pool through selective proliferation and retention within the tumor microenvironment (48). In the absence of Tregs, a new route of entry presents itself in the form of intratumoral HEVs, which are significantly associated with TIL frequency and control of tumor growth (6).…”

Section: Discussionmentioning

confidence: 99%

Treg Depletion Licenses T Cell–Driven HEV Neogenesis and Promotes Tumor Destruction

Colbeck

Jones

Hindley

et al. 2017

Cancer Immunology Research

Self Cite

103

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T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process which can increase frequencies of tumor-infiltrating lymphocytes (TILs) through promoting development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model, that allows for co-evolution of the tumor microenvironment and the immune response, to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on TNF receptor and independent of lymphotoxin β receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model where Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer.

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“…CD69 expression was studied by Colbeck et al[33] and they stated that Tregs expressing CD69(+) are more proliferative and more suppressive than their CD69(-) counterparts. This finding explains our results that showed significant lower CD69 expression in HCV patients with autoantibodies suggesting inhibition of Tregs activity favoring autoimmune environment.…”

Section: Discussionmentioning

confidence: 99%

Regulatory and activated effector T cells in chronic hepatitis C virus: Relation to autoimmunity

Fouad

Raziky

Hassan

et al. 2016

WJH

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AIMTo investigate how Tregs are regulated in chronic hepatitis C virus (HCV) patients via assessment of Tregs markers (granzyme 2, CD69 and FoxP3), Teffs markers [TNFRSF4 (OX40), INFG] and CD4, CD25 genes.METHODSA prospective study was conducted on 120 subjects divided into 4 groups: Group I (n = 30) treatment naïve chronic HCV patients; Group II (n = 30) chronic HCV treated with Peg/Riba; Group III (n = 30) chronic HCV associated with non-organ specific autoantibody and Group IV (n = 30) healthy persons as a control group. Tregs and Teffs markers were assessed in peripheral blood mononuclear cells by quantitative real time reverse transcriptase-polymerase chain reaction.RESULTSChronic HCV patients exhibited significant higher levels of both Teffs and Tregs in comparison to healthy control group. Tregs markers were significantly decreased in Peg/Riba treated HCV patients in comparison to treatment naïve HCV group. In HCV patients with antinuclear antibody (ANA) +ve, Tregs markers were significantly decreased in comparison to all other studied groups. Teffs markers were significantly elevated in all HCV groups in comparison to control and in HCV group with ANA +ve in comparison to treatment naïve HCV group.CONCLUSIONElevated Tregs cells in chronic HCV patients dampen both CD4+ and CD8+ autologous T cell immune response. Interferon-α and ribavirin therapy suppress proliferation of Tregs. More significant suppression of Tregs was observed in HCV patients with autoantibodies favoring pathological autoimmune response.

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Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors

Cited by 12 publications

References 37 publications

Stability and function of regulatory T cells expressing the transcription factor T-bet

Stability and function of regulatory T cells expressing the transcription factor T-bet

Treg Depletion Licenses T Cell–Driven HEV Neogenesis and Promotes Tumor Destruction

Regulatory and activated effector T cells in chronic hepatitis C virus: Relation to autoimmunity

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