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Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients

"VSports最新版本" Isabelle Magalhaes et al. J Clin Invest. 2015 Apr.

"VSports" Abstract

Obesity and type 2 diabetes (T2D) are associated with low-grade inflammation, activation of immune cells, and alterations of the gut microbiota. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial ligands, are present in blood and enriched in mucosal and inflamed tissues. Here, we analyzed MAIT cells in the blood and adipose tissues of patients with T2D and/or severe obesity. We determined that circulating MAIT cell frequency was dramatically decreased in both patient groups, and this population was even undetectable in some obese patients. Moreover, in both patient groups, circulating MAIT cells displayed an activated phenotype that was associated with elevated Th1 and Th17 cytokine production. In obese patients, MAIT cells were more abundant in adipose tissue than in the blood and exhibited a striking IL-17 profile. Bariatric surgery in obese patients not only improved their metabolic parameters but also increased circulating MAIT cell frequency at 3 months after surgery. Similarly, cytokine production by blood MAIT cells was strongly decreased after surgery. This study reveals profound MAIT cell abnormalities in patients harboring metabolic disorders, suggesting their potential role in these pathologies VSports手机版. .

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Figures

Figure 7
Figure 7. Increased frequency of circulating MAIT cells after bariatric surgery.
(A) Obese patients’ BMI before (pre-op; n = 62) and at 3, 6, and 12 months after surgery (post-op; n = 46, 47, and 39, respectively). †P < 0.0001. (B) HbA1c levels of obese patients with T2D before surgery (n = 19) and at 3, 6, and 12 months after surgery (n = 11, 12, and 9, respectively). **P = 0.003, ***P = 0.0005. (C and D) Circulating leptin and adiponectin levels in obese patients before (n = 52) and at 3, 6, and 12 months after surgery (n = 44, 46, and 39, respectively). †P < 0.0001. (E) Circulating MAIT cells frequency before (n = 69) and at 3, 6, and 12 months after surgery (n = 35, 34, and 35, respectively). (Control individuals, n = 23.) *P = 0.01, ***P < 0.002, †P < 0.0001. Circulating MAIT cell frequency was significantly lower in obese patients at each time point compared to control individuals (P < 0.05). (F) Cytokine production after PMA-ionomycin stimulation of MAIT cells from healthy individuals (n = 20) and obese patients before surgery (n = 39) and 3, 6, and 12 months after surgery (n = 38, 33, and 31, respectively). *P < 0.04, **P < 0.004, ***P = 0.0008, †P < 0.0001. Mann-Whitney U or Wilcoxon test.
Figure 6
Figure 6. Influence of AT samples on MAIT cell phenotype.
(A) PBMCs from healthy donors were cocultured with AT samples from obese patients, followed by flow cytometric analysis of Bcl-2 expression in MAIT cells. (B–D) Flow cytometric analysis of Bcl-2 and Ki-67 expression in MAIT cells. (B and C) Bcl-2 MFI and percent of Ki-67 expression in MAIT cells from peripheral blood and OM AT of 5 obese patients. (D) Bcl-2 MFI in Ki-67– and Ki-67+ MAIT cells from AT. MFI, median fluorescence intensity.
Figure 5
Figure 5. Cytokine production by MAIT cells in the AT of severely obese patients.
Analysis of T cell cytokine production by flow cytometry, after PMA-ionomycin stimulation. (A and B) MAIT cell cytokine production in (A) the OM AT of healthy donors (n = 7) and obese patients (Ob) (n = 31; *P < 0.05, **P < 0.01) and (B) the SC AT of healthy donors (n = 4) and obese patients (n = 7). (C) IL-17 production by various T cell subsets from OM AT from healthy donors and obese patients shown in A. Mann-Whitney U test.
Figure 4
Figure 4. MAIT cells in the AT of obese patients.
(A and B) Flow cytometry analysis of MAIT cells detected in the OM and SC AT. (A) Representative dot plots. (B) MAIT cell frequency in the blood, OM, and SC AT of healthy donors (n = 23, 7, and 4, respectively) and obese patients (n = 69, 31, and 7, respectively). †P < 0.0001. (C) MAIT cell frequency in paired blood and OM AT from 13 obese patients. (D) CD25 MAIT cell expression in OM AT of control individuals and obese patients (n = 5 and 17, respectively). (E) Frequency of T cell subsets in blood from control individuals (n = 15) and obese patients (n = 20) and in OM AT from obese patients (n = 13). *P < 0.04, †P < 0.0001. Mann-Whitney U test.
Figure 3
Figure 3. Defective activation of T2D patients’ MAIT cells after TCR triggering.
(A and B) ON stimulation with MAIT ligand at various concentrations (0–87.5 U/ml). (A) CD25 and CD69 expression on MAIT cells from controls (n = 5) and T2D patients (n = 7). (B) Cytokine production by MAIT cells from controls (n = 8) and T2D patients (n = 8). Blocking MR1 Ab was added when indicated. *P < 0.05, **P ≤ 0.005. Mann-Whitney U test.
Figure 2
Figure 2. Cytokine production by circulating MAIT cells in T2D and severe obesity.
(A and B) Analysis of circulating MAIT cell cytokine production by flow cytometry, after PMA-ionomycin stimulation. (A) Representative dot plot from an obese patient. (B) MAIT cell cytokine production in healthy donors (HD) (n = 20), nonobese T2D (n = 10), obese T2D (n = 27), and non-T2D obese patients (n = 31). *P ≤ 0.04, **P ≤ 0.007, ***P = 0.005, †P < 0.001. (C) Correlation between the frequency of IL-17–producing MAIT cells and MAIT cell frequency in patients (n = 67). Mann-Whitney U test and Spearman’s correlation.
Figure 1
Figure 1. Decreased frequency of circulating MAIT cells in T2D and obesity.
(A) Costaining of lean and obese adults’ PBMCs with anti-Vα7.2 and anti-CD161 antibodies and with the 6-HM–loaded MR1 tetramer. All the cells binding to the MR1-6-HM tetramer were CD161hiVα7.2+, and MAIT cells were stained only by the MR1 tetramer loaded with the 6-HM ligand, and not the 6-FP ligand. MAIT cells were either CD8+ or double negative. (B) Lower frequencies of circulating MAIT cells were detected in nonobese T2D (n = 10), obese (Ob) T2D (n = 37), and non-T2D obese patients (n = 52) as compared with nondiabetic, nonobese healthy controls (n = 23). Note that in 12 obese patients, circulating MAIT cell frequency was below detection limit (<0.001%). Frequencies below 0.001% were arbitrarily displayed at 0.0005 but not included in the median and statistical calculations. †P < 0.0001. Adjusting for age and sex in a linear regression model did not change the significance. (C) Correlation between BMI and MAIT cell frequency (n = 122). (D) CD25 expression on MAIT cells in controls (n = 19) and T2D obese patients (n = 16). (E) CD69 expression on MAIT cells in controls (n = 20) and T2D obese patients (n = 14). **P < 0.003. Mann-Whitney U test and Spearman’s correlation. Straight lines represent medians. BMI is shown as kg/m2.
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References (V体育平台登录)

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