The Role of Lymphocytes in Diet-Induced Metabolic Disease

Boston University Medical Campus, Boston MA

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): The appreciation of insulin resistance (IR) and type 2 diabetes (T2D) as chronic inflammatory diseases has necessitated development of the new field of immunometabolism, which will define the role of the immune system in metabolic disease. Recent animal studies have shown that inflammatory T cells and B cells play key roles in the development of IR in T2D. For example, T cell skewing towards the pro-inflammatory Th17 and Th1 subsets and elevated Th17/Th1 numbers in the expanding diet-induced obesity (DIO) mouse adipose tissue (AT) promotes inflammation, thus IR (1, 5). Importantly, Th17 and Th1 cells are major sources of IL-17 and IFN-¿, respectively, two pro-inflammatory, anti-adipogenic, IR-linked cytokines. Complementary studies showed loss of anti-inflammatory regulatory T cells (Tregs) increases AT inflammation and serum insulin levels, while gain of Treg function decreases AT inflammation and rescues glucose sensitivity. Together, these studies show a pro-inflammatory T cell balance plays important roles in IR. Similar approaches also show B cells promote inflammation and IR. Like these murine studies, our pioneering human immunometabolism work identified a pro-inflammatory T cell subset balance in blood from T2D patients: pro-inflammatory Th17 and Th1 cells are elevated, and anti-inflammatory Tregs are reduced. Furthermore, we found that blood B cells from T2D patients are pro-inflammatory. Importantly, new data show T cell/B cell interaction is critical for elevated Th17 function in T2D; thus we have initiated some of the first mechanistic immunometabolism studies in human samples. Taken together, our work indicates that detailed human immune cell analysis will identify new mechanisms of IR/T2D thus introduce new concepts in assessment and treatment strategies. Furthermore, detailed analysis of the human immune system in IR/T2D individuals is absolutely essential to justify attempts to harness the power of the immune system as a biomarker and/or treatment for T2D. We hypothesize that the elevated pro-inflammatory T cell function we have found in T2D 1. is similar in blood and AT from a single individual; 2. Predicts IR and/or AT function in obesity patients; and 3. Requires support from B cells, which can be safely ablated with FDA-approved drugs. Testing these hypotheses would assess the innovative possibility that a simple blood test (T cell subset analysis) can identify risk of transition from insulin-sensitive to IR. The availability of such a test would be a major advance with immediate clinical impact. In addition to preliminarily identifying a biomarker for the IS/IR transition, outcomes will address the novel possibility that existing B cell depletion drugs may prevent the IS/IR transition.