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Impaired coronary microcirculation in type 2 diabetic patients is associated with elevated circulating regulatory T cells and reduced number of IL-21R⁺ T cells.

von Scholten BJ, Rosendahl A, Hasbak P, Bergholdt R, Kjaer A, Rossing P, Hansen TW - Cardiovasc Diabetol (2016)

Bottom Line: Presence of T2D was associated with T cell attenuation characterized by reduced overall T cell, Th17, IL-21R(+), Treg's and TLR4(+) T cells, while the monocyte population showed enhanced TLR4 expression.Further, our data revealed reduced M1-like CD11c expression in T2D which was associated with impaired CFR.In contrast, we show, for the first time in T2D, increased TLR4 expression on CD8 T cells, increased Treg cell number and Treg maturation and reduced IL-21R expression on CD8 T cells to be functionally associated with impaired CFR.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetic Complications, Steno Diabetes Center, Niels Steensens Vej 1, 2820, Gentofte, Denmark. bjos@steno.dk.

ABSTRACT

Background: Low-grade systemic inflammation is considered to participate in the progression of type 2 diabetes (T2D) and in diabetic complications.

Methods: To determine if circulating leukocytes were abnormally regulated in T2D patients, 8-color flow-cytometry (FACS) analysis was performed in a cross-sectional study of 37 T2D patients and 16 controls. Data obtained from the FACS analysis were compared to coronary flow reserve (CFR), assessed by Rb(82)-PET-imaging, to uncover inflammatory signatures associated with impaired CFR.

Results: Presence of T2D was associated with T cell attenuation characterized by reduced overall T cell, Th17, IL-21R(+), Treg's and TLR4(+) T cells, while the monocyte population showed enhanced TLR4 expression. Further, our data revealed reduced M1-like CD11c expression in T2D which was associated with impaired CFR. In contrast, we show, for the first time in T2D, increased TLR4 expression on CD8 T cells, increased Treg cell number and Treg maturation and reduced IL-21R expression on CD8 T cells to be functionally associated with impaired CFR.

Conclusions: Our demonstration that HbA1c inversely correlates to several T cell populations suggests that T cells may play disease modulating roles in T2D. Further, the novel association between impaired CFR and regulatory T cells and IL-21R(+) T cells imply an intricate balance in maintaining tissue homeostasis in vascular diabetic complications.

No MeSH data available.


Related in: MedlinePlus

Total number of circulating monocyte populations in diabetic patients and healthy controls. The number of CD68+ monocytes (a), M0-like CD14+CD16− monocytes (b), M2-like CD14+CD16+ monocytes (c) and M1-like CD14dimCD16+ monocytes (d) is shown. A total of 2 ml blood was analysed and the total number of each cell population was calculated as described in the “Methods” section. Each dot represents one individual and the horizontal line represents the mean value in each group. P values represent difference between groups assessed by t test
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Fig4: Total number of circulating monocyte populations in diabetic patients and healthy controls. The number of CD68+ monocytes (a), M0-like CD14+CD16− monocytes (b), M2-like CD14+CD16+ monocytes (c) and M1-like CD14dimCD16+ monocytes (d) is shown. A total of 2 ml blood was analysed and the total number of each cell population was calculated as described in the “Methods” section. Each dot represents one individual and the horizontal line represents the mean value in each group. P values represent difference between groups assessed by t test

Mentions: Healthy subjects and T2D patients in our cohort both had approximately 300 monocytes/μl blood (Fig. 4a). Analysis of the monocyte compartment using the CD14 and CD16 expression profile as functional markers of M1- and M2-like polarization [19, 20] uncovered a disease specific regulation of the polarization signature (Fig. 4b–d). The undifferentiated CD14+CD16− M0-like monocytes, show a moderate reduction in T2D blood compared to healthy subjects (257 ± 9 and 294 ± 20/µl respectively), while the M2-like CD14+CD16+ cells show no difference between the groups (Fig. 4b, c). Most interestingly, the M1-like CD14dimCD16+ monocytes, showed a strong and highly significant reduction (p < 0.001) in the T2D patients compared to the healthy subjects (30 ± 2 vs 44 ± 3/µl respectively) (Fig. 4d). No difference between groups was observed after adjusting for age, sex, body mass index, and smoking (p ≥ 0.16; Table 2). In contrast, a significant difference remained between healthy and T2D patients also after adjustment in the M1-like subset of monocytes (p = 0.006; Table 2). To further evaluate the reduction of M1-like monocytes, expression of the M1-associated cell marker CD11c on the monocyte subsets was performed. As expected, no modulation of CD11c expression on the M2- and M0-like monocyte subsets or on the total monocyte population was identified (Fig. 5a–c). In sharp contrast, the remaining CD14dimCD16+ M1-like monocytes showed a highly significant increase of CD11c surface expression suggesting that although the cell population as such is reduced the remaining cells have augmented capacity to respond in a pro-inflammatory manner (Fig. 5d). When performing adjustment for age, sex, body mass index and smoking, this increase of CD11c surface expression remained significant (p = 0.031; Table 2).Fig. 4


Impaired coronary microcirculation in type 2 diabetic patients is associated with elevated circulating regulatory T cells and reduced number of IL-21R⁺ T cells.

von Scholten BJ, Rosendahl A, Hasbak P, Bergholdt R, Kjaer A, Rossing P, Hansen TW - Cardiovasc Diabetol (2016)

Total number of circulating monocyte populations in diabetic patients and healthy controls. The number of CD68+ monocytes (a), M0-like CD14+CD16− monocytes (b), M2-like CD14+CD16+ monocytes (c) and M1-like CD14dimCD16+ monocytes (d) is shown. A total of 2 ml blood was analysed and the total number of each cell population was calculated as described in the “Methods” section. Each dot represents one individual and the horizontal line represents the mean value in each group. P values represent difference between groups assessed by t test
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837587&req=5

Fig4: Total number of circulating monocyte populations in diabetic patients and healthy controls. The number of CD68+ monocytes (a), M0-like CD14+CD16− monocytes (b), M2-like CD14+CD16+ monocytes (c) and M1-like CD14dimCD16+ monocytes (d) is shown. A total of 2 ml blood was analysed and the total number of each cell population was calculated as described in the “Methods” section. Each dot represents one individual and the horizontal line represents the mean value in each group. P values represent difference between groups assessed by t test
Mentions: Healthy subjects and T2D patients in our cohort both had approximately 300 monocytes/μl blood (Fig. 4a). Analysis of the monocyte compartment using the CD14 and CD16 expression profile as functional markers of M1- and M2-like polarization [19, 20] uncovered a disease specific regulation of the polarization signature (Fig. 4b–d). The undifferentiated CD14+CD16− M0-like monocytes, show a moderate reduction in T2D blood compared to healthy subjects (257 ± 9 and 294 ± 20/µl respectively), while the M2-like CD14+CD16+ cells show no difference between the groups (Fig. 4b, c). Most interestingly, the M1-like CD14dimCD16+ monocytes, showed a strong and highly significant reduction (p < 0.001) in the T2D patients compared to the healthy subjects (30 ± 2 vs 44 ± 3/µl respectively) (Fig. 4d). No difference between groups was observed after adjusting for age, sex, body mass index, and smoking (p ≥ 0.16; Table 2). In contrast, a significant difference remained between healthy and T2D patients also after adjustment in the M1-like subset of monocytes (p = 0.006; Table 2). To further evaluate the reduction of M1-like monocytes, expression of the M1-associated cell marker CD11c on the monocyte subsets was performed. As expected, no modulation of CD11c expression on the M2- and M0-like monocyte subsets or on the total monocyte population was identified (Fig. 5a–c). In sharp contrast, the remaining CD14dimCD16+ M1-like monocytes showed a highly significant increase of CD11c surface expression suggesting that although the cell population as such is reduced the remaining cells have augmented capacity to respond in a pro-inflammatory manner (Fig. 5d). When performing adjustment for age, sex, body mass index and smoking, this increase of CD11c surface expression remained significant (p = 0.031; Table 2).Fig. 4

Bottom Line: Presence of T2D was associated with T cell attenuation characterized by reduced overall T cell, Th17, IL-21R(+), Treg's and TLR4(+) T cells, while the monocyte population showed enhanced TLR4 expression.Further, our data revealed reduced M1-like CD11c expression in T2D which was associated with impaired CFR.In contrast, we show, for the first time in T2D, increased TLR4 expression on CD8 T cells, increased Treg cell number and Treg maturation and reduced IL-21R expression on CD8 T cells to be functionally associated with impaired CFR.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetic Complications, Steno Diabetes Center, Niels Steensens Vej 1, 2820, Gentofte, Denmark. bjos@steno.dk.

ABSTRACT

Background: Low-grade systemic inflammation is considered to participate in the progression of type 2 diabetes (T2D) and in diabetic complications.

Methods: To determine if circulating leukocytes were abnormally regulated in T2D patients, 8-color flow-cytometry (FACS) analysis was performed in a cross-sectional study of 37 T2D patients and 16 controls. Data obtained from the FACS analysis were compared to coronary flow reserve (CFR), assessed by Rb(82)-PET-imaging, to uncover inflammatory signatures associated with impaired CFR.

Results: Presence of T2D was associated with T cell attenuation characterized by reduced overall T cell, Th17, IL-21R(+), Treg's and TLR4(+) T cells, while the monocyte population showed enhanced TLR4 expression. Further, our data revealed reduced M1-like CD11c expression in T2D which was associated with impaired CFR. In contrast, we show, for the first time in T2D, increased TLR4 expression on CD8 T cells, increased Treg cell number and Treg maturation and reduced IL-21R expression on CD8 T cells to be functionally associated with impaired CFR.

Conclusions: Our demonstration that HbA1c inversely correlates to several T cell populations suggests that T cells may play disease modulating roles in T2D. Further, the novel association between impaired CFR and regulatory T cells and IL-21R(+) T cells imply an intricate balance in maintaining tissue homeostasis in vascular diabetic complications.

No MeSH data available.


Related in: MedlinePlus