Abstract
The immune system plays a significant role in controlling systemic metabolism. Innate-like T (ILT) cells in particular, such as mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells and γδ T cell receptor expressing cells, have been reported to promote metabolic homeostasis. However, these different ILT cell subsets have, to date, been generally studied in isolation. Here we conducted a pilot study assessing the phenotype and function of circulating MAIT, iNKT, and Vδ2+ T cells in a small cohort of 10 people with obesity and type 2 diabetes (T2D), 10 people with obesity but no diabetes, and 12 healthy individuals. We conducted phenotypic analysis by flow cytometry ex vivo, and then functional analysis after in vitro stimulation using either PMA/ionomycin or synthetic agonists, or precursors thereof, for each of the cell-types; use of the latter may provide important knowledge for the development of novel therapeutics aimed at activating human ILT cells. The results of our pilot study, conducted on circulating cells, show clear dysfunction of all three ILT cell subsets in obese and obese T2D patients, as compared to healthy controls. Importantly, while both iNKT and Vδ2+ T cell dysfunctions were characterized by diminished IL-2 and interferon-γ production, the distinct dysfunctional state of MAIT cells was instead defined by skewed subset composition, heightened sensitivity to T cell receptor engagement and unchanged production of all measured cytokines.
Highlights
Unconventional, innate-like T (ILT) cells are generally defined as subsets of T lymphocytes recognizing conserved, non-peptide antigens in the context of monomorphic major histocompatibility complex (MHC) related or unrelated molecules
Our pilot study partly supports previously described patterns of mucosal-associated invariant T (MAIT) cell dysfunction in metabolic disease, with some discrepancies, but more importantly provides novel and comparative data related to obesity/type 2 diabetes (T2D) related dysfunction of human invariant natural killer T (iNKT) and Vδ2+ T cells, to date scarcely characterized
A notable discrepancy between our data and the study by Magalhaes et al [14] is that we did not find MAIT cells from obese and obese/T2D patients to be refractory to T cell receptor (TCR) stimulation
Summary
Unconventional, innate-like T (ILT) cells are generally defined as subsets of T lymphocytes recognizing conserved, non-peptide antigens in the context of monomorphic major histocompatibility complex (MHC) related or unrelated molecules. In humans, these include mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells and Vγ9+Vδ2+ T cells, which feature prominent roles in microbial immunity and characteristic PLZF (promyelocytic leukemia zinc finger, Zbtb16)-dependent innate-like effector programs [1, 2]. MAIT cells target riboflavin metabolites derived from bacteria or yeast [3] presented in the context of MHC-related molecule 1 (MR1) [4, 5], while iNKT cells and Vγ9+Vδ2+ T cells recognize microbial lipid antigens presented by CD1d [6], and bacterial and neoplastic. Few studies have investigated Vγ9+Vδ2+ T cells in the context of metabolic disease in humans [16, 20]
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