Control of regulatory T cell homeostasis

Buszko, Maja; Shevach, Ethan M.

doi:10.1016/j.coi.2020.07.001

Cited by 18 publications

(16 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tregs, including T FR cells, must maintain their suppressive anergic phenotype during ongoing inflammatory responses [11,13,28]. This functional stability reflects a lack of effector activity by Tregs (i.e., expression of proinflammatory cytokines) and may or may not require stable FoxP3 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Because stable FoxP3 expression in Tregs may resume with the resolution of inflammation [44], it is unclear if the above mechanism remains operational during the remission phase of the disease. Despite that complete demethylation of the conserved non-coding sequence 2 (CNS2), also known as Treg cell-specific demethylated region (TSDR), in the first intron of the FoxP3 locus is required for optimal expression of FoxP3 [13,45], Tregs with a fully demethylated TSDR still lose FoxP3 expression and become exTregs in a MOG-EAE model [44], suggesting that lack of epigenetic imprinting in the CNS2 may not always be the leading cause of FoxP3 loss in Tregs during EAE [44]. The above considerations along with our finding that Prdm1 fl/fl FoxP3 YFP-Cre mice failed to recover from EAE suggest that stage-specific genetic and epigenetic elements may regulate Blimp1-dependent Treg stability during EAE.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have emphasized this critical aspect of T FR cells, as selective deletion of T FR cells has a profound impact on immune responses, leading to the aberrant expansion of T FH cells and excessive Ab production [10]. Like other Treg subsets, T FR cells must maintain their suppressive anergic phenotype during ongoing inflammatory responses and destabilized T FR cells become ex-T FR cells that acquire effector cell activity [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

Luo

Dixon

et al. 2021

J Neuroinflammation

View full text Add to dashboard Cite

Background Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Methods To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. Results Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Conclusions Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

Luo

Dixon

et al. 2021

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Each subset of immune cells in the TME utilizes different metabolic programs for their survival, activation, and differentiation [18,19]. Effector T-cells are highly glycolytic, but Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) [20][21][22][23]. Activated dendritic cells use glycolysis predominantly, and pro-in ammatory tumor-associated macrophages (TAMs) are highly glycolytic.…”

Section: Introductionmentioning

confidence: 99%

High Tumor Hexokinase-2 Expression Promotes a Pro-tumorigenic Immune Microenvironment by Modulating CD8+/regulatory T-cell Infiltration

Kim

Koh

Song

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Relationship between cancer cell glycolysis and the landscape of tumor immune microenvironment in human cancers was investigated. Methods: Forty-one fresh lung adenocarcinoma (ADC) tissues were analyzed using flow cytometry for comprehensive immunoprofiling. Formalin-fixed tissues were immunostained for hexokinase-2 (HK2) to assess cancer cell glycolysis. For validation, formalin-fixed tissues from 375 lung ADC, 118 lung squamous cell carcinoma (SqCC), 338 colon ADC, and 78 lung cancer patients treated with anti-PD-1/PD-L1 immunotherapy were immunostained for HK2, CD8, and FOXP3.Results: Based on immunoprofiling of lung ADC, HK2 tumor expression was associated with the composition of lymphoid cells rather than myeloid cells. High HK2 tumor expression was associated with immunosuppressive/pro-tumorigenic features, especially decreased ratio of CD8+ T-cells to Tregs (rho=-0.415, P=0.012). This correlation was also confirmed in four different cohorts including lung ADC and SqCC, colon ADC, and the immunotherapy cohort (rho=-0.175~-0.335, all P<0.05). A low CD8+ T-cell to Treg ratio was associated with poor progression-free survival and overall survival in lung SqCC patients, and a shorter overall survival in the immunotherapy cohort (all, P<0.05). Conclusions: An increase in HK2 expression may contribute to shaping the immunosuppressive/pro-tumorigenic tumor microenvironment by modulating the CD8+ T-cell to Treg ratio. Targeting tumor HK2 expression might be a potential strategy for enhancing anti-tumor immunity.

show abstract

“…One of the most important subpopulations of T cells are T regulatory cells (Tregs). They are characterized by the ability to suppress the immune response, which is of great importance in maintaining homeostasis and in autoimmune phenomena (4)(5)(6)(7)(8)(9)(10). Tregs are involved in inhibiting the suppressive activity of T cells and the prevention of autoimmune diseases (9).…”

mentioning

confidence: 99%