Altered CD161bright CD8+ Mucosal Associated Invariant T (MAIT)-Like Cell Dynamics and Increased Differentiation States among Juvenile Type 1 Diabetics

Abstract

Type 1A diabetes (T1D) is believed to be caused by immune-mediated destruction of β-cells, but the immunological basis for T1D remains controversial. Microbial diversity promotes the maturation and activation of certain immune subsets, including CD161bright CD8+ mucosal associated invariant T (MAIT) cells, and alterations in gut mucosal responses have been reported in type 1 diabetics (T1Ds). We analyzed T cell populations in peripheral blood leukocytes from juvenile T1Ds and healthy controls. We found that proportion and absolute number of MAIT cells were similar between T1Ds and controls. Furthermore, while MAIT cell proportions increased with age among healthy controls, this trend was not observed among long-standing T1Ds. Additionally, the CD27- MAIT cell subset is significantly increased in T1Ds and positively correlated with HbA1c levels. However, after T1Ds are stratified by age, the younger group has significantly increased proportions of CD27- MAIT cells compared to age-matched controls, and this proportional increase appears to be independent of HbA1c levels. Finally, we analyzed function of the CD27- MAIT cells and observed that IL-17A production is increased in CD27- compared to CD27+ MAIT cells. Overall, our data reveal disparate MAIT cell dynamics between T1Ds and controls, as well as signs of increased MAIT cell activation in T1Ds. These changes may be linked to hyperglycemia and increased mucosal challenge among T1Ds.

Human blood MAIT cell subsets defined using MR1 tetramers

“…MR1‐5‐OP‐RU tetramers now permit the identification of MAIT cells based on their MR1‐restricted TCR specificity. Because many clinical studies have used surrogate phenotyping techniques, and often only focus on CD8 + MAIT cells in their analysis, we felt it was important to determine how well these approaches compare to the use of MR1 tetramers to examine all MAIT cell populations. Here, we analyzed a large cohort of healthy human PBMC samples to both establish the phenotypic characteristics of human MAIT cells, and subsets thereof, using MR1‐5‐OP‐RU tetramers, as well as to establish a comparison of the use of MR1‐5‐OP‐RU tetramers with surrogate mAb‐based identification techniques.…”

“…MAIT cells also appear to be perturbed in several noninfectious diseases, including autoimmunity, metabolic disorders and cancer, as well as viral infection . With growing interest in the field of MAIT cell biology, correct identification of MAIT cells is critical to determine their role in health and disease.…”

iNKT and MAIT Cell Alterations in Diabetes

“…In humans, MAIT cells are identified using anti-Vα7.2 TCR chain and anti-CD161 antibodies. A recent report analyzed that the CD161 bright CD8 + T cell subset in juvenile T1D patients ( 51 ), with the CD161 bright CD8 + T cells displaying a phenotype, IL-18Rα + , CD127 + , CD45RA − , and CCR7 − , suggestive of MAIT cells. No difference in the CD161 bright CD8 + T cell frequency was observed in juvenile T1D patients as compared to age-matched controls.…”

No Evidence for Presence of Mucosal-Associated Invariant T Cells in the Insulitic Lesions in Patients Recently Diagnosed with Type 1 Diabetes

“…17 The notion that MAIT cell numbers and phenotype are influenced to a large extent by impairment of glucose metabolism is further supported by the correlation between MAIT cell numbers and their phenotype to the hemoglobin A1c levels in children with T1D. 18 Thus, it is possible that the increased MAIT cell activation and reduced circulating numbers observed in children with T1D may be directly linked to hyperglycemia rather than being part of the b-cell destructive process.…”