Regulatory T Cells Control Effector T Cell Inflammation in Human Prediabetes

Li, Rui; Pugh, Gabriella H.; Tevonian, Erin; Thompson, Katherine; Lauffenburger, Douglas A.; Kern, Philip A.; Nikolajczyk, Barbara S.

doi:10.2337/db21-0659

Cited by 14 publications

(28 citation statements)

References 32 publications

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“…To determine the relative contributions of myeloid and T cells to Figure 1G). We conclude, from both CD3/CD28-and LPS-elicited profiles, that metabolic status impacts cytokine competency in cells from donors with obesity, consistent with our work on purified CD4 + T cells [30].…”

Section: Pbmcs Increase Cytokine Production With Time Following T Cel...supporting

confidence: 88%

“…Responses to T cell-targeted CD3/CD28 underscored the distinctiveness of preT2D inflammation first indicated by our analysis of cytokine competency of purified CD4 + T cells [30] and significantly extends existing analyses of cytokines in preT2D plasma/serum [39,40]. The acute myeloid response, combined with the more sustained response to CD3/CD28 that dominates overall "inflammation" at 72 hours, is consistent with a canonical immune response in which innate immune cells respond quickly to prime a sustained adaptive immune response.…”

Section: T Cell Cytokine Competency Disproportionately Contributes To...supporting

confidence: 54%

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T cells dominate peripheral inflammation in a cross‐sectional analysis of obesity‐associated diabetes

Pugh

Calvo

Agrawal

et al. 2022

Obesity

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Objective Myeloid cells dominate metabolic disease‐associated inflammation (metaflammation) in mouse obesity, but the contributions of myeloid cells to the peripheral inflammation that fuels sequelae of human obesity are untested. This study used unbiased approaches to rank contributions of myeloid and T cells to peripheral inflammation in people with obesity across the spectrum of metabolic health. Methods Peripheral blood mononuclear cells (PBMCs) from people with obesity with or without prediabetes or type 2 diabetes were stimulated with T cell‐targeting CD3/CD28 or myeloid‐targeting lipopolysaccharide for 20 to 72 hours to assess cytokine production using Bio‐Plex. Bioinformatic modeling ranked cytokines with respect to their predictive power for metabolic health. Intracellular tumor necrosis factor α was quantitated as a classical indicator of metaflammation. Results Cytokines increased over 72 hours following T cell‐, but not myeloid‐, targeted stimulation to indicate that acute myeloid inflammation may shift to T cell inflammation over time. T cells contributed more tumor necrosis factor α to peripheral inflammation regardless of metabolic status. Bioinformatic combination of cytokines from all cohorts, stimuli, and time points indicated that T cell‐targeted stimulation was most important for differentiating inflammation in diabetes, consistent with previous identification of a mixed T helper type 1/T helper type 17 cytokine profile in diabetes. Conclusions T cells dominate peripheral inflammation in obesity; therefore, targeting T cells may be an effective approach for prevention/management of metaflammation.

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Section: Pbmcs Increase Cytokine Production With Time Following T Cel...supporting

confidence: 88%

Section: T Cell Cytokine Competency Disproportionately Contributes To...supporting

confidence: 54%

T cells dominate peripheral inflammation in a cross‐sectional analysis of obesity‐associated diabetes

Pugh

Calvo

Agrawal

et al. 2022

Obesity

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“…The authors stimulated cells with CD3/CD28 beads for 40 hr and then quantified secreted cytokines in a 25-cytokine multiplex ( Ip et al, 2016 ; Beste et al, 2014 ; Lau et al, 2012 ). IL-10 was produced in greater amounts from cells of lean/healthy donors, and there were differences in production of Th1/Th17 cytokines, that is, more CCL-20, TNFα, GM-CSF in prediabetes, and less IL-6/-12 were noted ( Liu et al, 2022 ). These data are consistent with the tenet that metabolic status, independent of age, significantly shifts inflammatory profiles.…”

Section: Metabolic Dysfunction and Acute Sars-cov-2mentioning

confidence: 99%

Post-acute sequelae of COVID-19: A metabolic perspective

Scherer

Kirwan

Rosen

2022

eLife

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The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.

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“…CD4 + T cells influence obesity-associated inflammation, especially the systemic inflammation that provokes numerous obesity comorbidities in people. A recent study showed that CD4 + T cells from subjects with prediabetes produces a unique inflammatory profile [48]. A better understanding of CD4 + T change in prediabetes is also important for clarifying the gut microbiota-host immunity interaction in metabolic disease.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Tangning Ziyabitusi on Gut Microbiota and T lymphocyte Subsets in Impaired Glucose Regulation Rats

Zhao¹,

Nuli²,

Jiao³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background: Impaired glucose regulation (IGR) represents the prediabetic state and is associated with gut microbiota (GM) dysbiosis and chronic inflammation. Tangning Ziyabitusi Tablet (TZT) is a Chinese Uyghur herbal medicine with preventative and therapeutic effects on diabetes, but its hypoglycemic mechanisms are unclear. Methods: Thirty-six male Wistar rats were divided into the normal diet (ND) and IGR groups. The IGR group was given a high-fat diet (HFD). After the IGR model establishment, the ND group was divided into ND and ND+TZT groups, and the IGR group into IGR and IGR+TZT groups. After 8 weeks of TZT administration, 16S rRNA sequencing and untargeted metabolomics were performed on fecal samples. Mesenteric lymph nodes were also collected, and T lymphocytes separated after rats were sacrificed. Flow cytometry was used to characterize different CD4 + T cell subsets in mesenteric lymph nodes. Finally, we analyzed the correlation between GM and characteristic fecal metabolites. Results: Impaired glucose tolerance and insulin resistance were improved in the IGR+TZT group when compared with the IGR group. Bacterial 16S rRNA sequencing results showed that Sobs and Chao1 indices in the IGR group were significantly decreased, but were increased in the IGR+TZT group. The relative abundance of Bacteroidetes was decreased while the relative abundance of Firmicutes was increased in the IGR group. Adlercreutzia abundance was decreased after TZT administration, while the abundance of Christensenellaceae_R-7_group, norank_f_norank_o_Clostridia_UCG-014, UCG-005, and Eubacterium_nodatum_group was increased in the IGR+TZT group. Lymph node CD4 + T cell proportions in the IGR group were significantly increased, while they were significantly decreased in the IGR+TZT group. Correlation analysis showed that tumor necrosis factor-α, interleukin-6, T helper cells (Th1, Th2, Treg), and insulin had a greater impact on GM community structure. Conclusions: TZT improved glucose tolerance and ameliorated GM dysbiosis in IGR rats. Additionally, TZT significantly modulated CD4 + T cell subset proportions in rat mesenteric lymph nodes and fecal metabolism. Moreover, correlation analysis showed that key microbiota was closely related to IGR indices. Thus, TZT modulated GM composition and immune functions of the intestinal mucosa. We provide useful information for the investigation of active mechanisms and the clinical application of TZT.

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Regulatory T Cells Control Effector T Cell Inflammation in Human Prediabetes

Cited by 14 publications

References 32 publications

T cells dominate peripheral inflammation in a cross‐sectional analysis of obesity‐associated diabetes

T cells dominate peripheral inflammation in a cross‐sectional analysis of obesity‐associated diabetes

Post-acute sequelae of COVID-19: A metabolic perspective

The Effects of Tangning Ziyabitusi on Gut Microbiota and T lymphocyte Subsets in Impaired Glucose Regulation Rats

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