T cells are implicated in the pathogenesis of autoimmune diabetes in both animal models and in humans with T1D. No difference in the total number of CD4+ T cells has been identified between individuals with and without T1D. Some studies have found alterations in the relative number of CD4/CD8 T cells and alterations in the memory compartment in individuals with T1D;however, no consistent pattern has been described. While lack of Treg unambiguously results in the early onset of autoimmune diabetes in both mouse and man, most studies have found no difference in the number of Treg present in peripheral blood of humans with and without disease. In contrast to these static measurements of CD4+ T cell number, there are indications that altered responses to antigenic stimuli, IL-2, and IL-15 may impact differentiation, stability and proliferation of CD4+ T cells in autoimmune diabetes. We and others have found evidence of impaired signaling through the IL-2R, and diminished maintenance of FOXP3 expression in T1D subjects consistent with studies in mice which suggest Treg turnover may have important implications for the durability of immune tolerance. In addition we have shown that responses to IL-15 in T1D are also blunted. Both IL-2 and IL-15 are among the cytokines that influence memory T-cell homeostasis. These and other factors may influence the homeostatic proliferation in the memory pool. Assessments of T cell proliferation and survival in vitro may not correlate with in vivo measures. FoxP3+ Treg are anergic in vitro but there are indications that Treg are among the more proliferative cells in vivo. Further, Treg from both NOD mice and human type 1 diabetes subjects expand and function in vitro but there are indications that analogous cells in vivo have impaired phenotypic stability and function. These data suggest that robust, longitudinal, in vivo analyses are needed in order to fully understand CD4+ T cell homeostasis in type 1 diabetes. Advances in stable isotope methodologies (labeling with deuterium oxide (2H2O) and deuterated glucose (2H2-glucose) are used to measure the kinetics of cell populations in vivo in humans. We found that CD4+ memory T cells had greater in vivo turnover as measured by replacement, proliferation, and disappearance rates in T1D as compared with healthy control subjects. In this proposal, we aim to evaluate in vivo T cell kinetics in individuals at risk for type 1 diabetes identified by Diabetes TrialNet and healthy control subjects.
Specific Aims :
Aim 1 : To determine whether altered T cell kinetics is present prior to diagnosis in individuals at risk for type 1 diabetes.
Aim 2 : To determine the changes in T cell kinetics over time.
Type 1 diabetes mellitus (T1DM) is an immune-mediated disease of children and adults in which insulin-producing beta cells are completely or near completely destroyed, resulting in life-long dependence on exogenous insulin. Despite improved treatments, individuals with type 1 diabetes still face significant morbidity and early mortality;thus, prevention of the onset of the disease would represent a significant advancement. Studying how immune cells grow and survive within individuals at risk for T1D will increase our understanding of the causes of disease, and may serve as a biomarker to predict disease risk and facilitate testing of novel therapies to prevent T1D.