Decreased CD127 Expression on CD4+ T-Cells and Elevated Frequencies of CD4+CD25+CD127− T-Cells in Children with Long-Lasting Type 1 Diabetes

Abstract

Pathobiology of type 1 diabetes (T1D) is predominantly associated with T-cell-related actions. Homeostasis of majority of T-cells is critically dependent on signals mediated by CD127 (interleukin-7 receptor, IL-7R). In contrast, regulatory T-cells express very little CD127 and thereby may be delineated by CD4+CD25+CD127− phenotype. Here we aimed to analyze CD127 expression on CD4+ and CD8+ T-cells and enumerate CD4+CD25+CD127− T-cells in long-lasting T1D. T-cells were analyzed by flow cytometry and immunologic data were correlated with vascular, metabolic, and inflammatory parameters. We demonstrated significantly decreased CD127 levels on CD4+, but not CD8+, T cells in T1D pediatric patients. Interestingly, frequencies of CD4+CD25+CD127− T-cells were significantly enhanced in T1D children and correlated well with frequencies of CD34+CD144+ endothelial progenitor cells and CD4+CD25− T-cells. Levels of CD127 on both CD4+ and CD8+ T-cells in T1D patients were not correlated to each other or HbA1C. Interestingly, however, CD127 levels on CD4+ T-cells were significantly correlated to frequencies of CD4+CD25+CD127− T-cells, whereas CD127 levels on CD8+ T-cells were significantly correlated to concentrations of VEGF and triglycerides. Our data indicate that CD127 expression is differentially modulated on CD4+ and CD8+ T-cells in the course of T1D. Moreover, we demonstrated that, in contrast to recent-onset T1D, long-lasting T1D is associated with enhancement of T-cells with regulatory phenotype.

Expression of PD-1 Molecule on Regulatory T Lymphocytes in Patients with Insulin-Dependent Diabetes Mellitus

“…After six days, CD8 + T cells ( Figure S3 C, Kolmogorov-Smirnov test p > 0.10; unpaired t test with Welch’s correction p = 0.9824), Treg cells ( Figure S3 D, Kolmogorov-Smirnov test p > 0.10; unpaired t test with Welch’s correction p < 0.0001), Teff cells ( Figure S3 E, Kolmogorov-Smirnov test p < 0.05; Mann Whitney test p = 0.0025), and Treg/Teff ratio ( Figure S3 F, Kolmogorov-Smirnov test p > 0.10; unpaired t test with Welch’s correction p = 0.0002), showed similar results to those obtained after four days. No correlation was observed between immune cell subsets and HbA1c values ( Table S1 ) in agreement with the results of previous studies in established T1D patients [ 10 , 11 ].…”

“…According to these studies, the number and frequency of peripheral Tregs were slightly high, significantly low or were normal in T1D patients [ 4 ]. Defective or normal suppressive function of Tregs were also reported [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. It must be highlighted, however, that these discrepancies may derive from the fact that different studies utilized either peripheral blood lymphocytes or lymphocytes residing within lymph nodes, or were carried out on samples from new onset or long-standing diabetics of different age or ethnic origin.…”

Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry

“…It has been described that the expression of CD25 and/or CD127 can be altered in (chronic) inflammatory/autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes, thereby influencing reliable Treg enumeration [ 12 , 26 , 31 ]. In addition, changes in CD25 and CD127 expressions have also been observed in cancer patients undergoing immunotherapeutic interventions such as vaccination or ipilimumab treatment [ 32 – 35 ].…”

OMIP‐053: Identification, Classification, and Isolation of Major FoxP3 Expressing Human CD4+ Treg Subsets

“…This has hampered the meaningful interpretation of study results as it poses problems for the generalizability and validity of claims of reliable Treg identification. An additional problem may be disease‐innate alterations in expression levels of molecules currently used to define Treg, such as CD127 and CD25 in chronic inflammatory/autoimmune diseases, following therapeutic interventions in cancer immunotherapy, or the absence of certain Treg subpopulations in tumor samples, for example, FoxP3 int /CD45RA pos . In human systemic lupus erythematous (SLE), for instance, CD25 expression may be high but not necessarily reflecting an increase in Treg numbers, necessitating the inclusion of non‐CD25 containing marker combinations (e.g., FoxP3/HELIOS) for a more reliable and differentiated approach toward Treg phenotyping and enumeration .…”