Hans Dooms, PhD

Email: hdooms@bu.edu
Institution: Boston University
Research: Dysregulation of autoreactive T cells in Type 1 Diabetes
Categories: BU

The Dooms laboratory focuses on understanding how autoreactive, islet-specific T cells, which are present in healthy people without causing harm, acquire their pathogenic functions and cause Type 1 Diabetes (T1D) when present in genetically susceptible individuals. The broad hypothesis is that faulty exposures and/or responses of T cells to microenvironmental factors such as cytokines and metabolites compromise immunoregulatory mechanisms and promote activation, differentiation and expansion of autoreactive T cells. The lab uses the non-obese diabetic (NOD) mouse model and patient samples to study this question in T1D. Currently, there are two active T1D projects in the lab:

Mechanisms underlying the role of Interleukin-7 in T1D: Interleukin-7 (IL-7) is a cytokine with critical functions in many aspects of T cell biology, from early T cell development to mature T cell homeostasis and function (1). Evidence for a critical role of the IL-7/IL-7Rα axis in the pathogenesis of multiple autoimmune diseases, including T1D, is accumulating (1), and, as a result, clinical trials targeting IL-7Rα are underway. We first demonstrated that a monoclonal antibody blocking IL-7Rα prevented T1D development and reversed established disease in NOD mice by inhibiting memory T cells (2). Mechanistically, we showed that treatment with anti-IL-7Rα antibodies increased expression of co-inhibitory receptors such as PD-1, affecting T cell effector functions (3). Our current research efforts are centered around the hypothesis that aberrant IL-7 signaling due to genetic variations in signaling and/or increased exposure in the steady-state and at the inflammatory site promotes metabolic fitness and prevents exhaustion in diabetogenic T cells. In addition, we are interested in developing new strategies to utilize IL-7Rα blockade in combination with autoantigen vaccination for the treatment of T1D (4).

The dietary fatty acid linoleic acid promotes pathogenic T cells in T1D: The incidence of T1D has globally been rising over the last 30 years, up to 5.3% annually in the United States, indicating that changing environmental conditions contribute to enhanced disease risk in genetically susceptible individuals. The nature of these environmental drivers, as well as the mechanisms by which they operate, remain largely undefined. The Western diet is one external factor that has emerged as a plausible candidate to promote autoimmune diseases, including T1D. One component of this diet that has garnered attention is the essential ω-6 polyunsaturated fatty acid linoleic acid (LA), which is present at increasingly high levels in the diet and has been associated with pro-inflammatory cytokine production. Our current research efforts are focused on our findings that exposure of autoreactive T cells to LA during activation changes their cytokine production profiles promoting a more diabetogenic phenotype. Thus, increasing levels of LA may promote the autoimmune response in T1D.