The autoimmune pathogenesis of Type 1 diabetes (T1D), the leading childhood autoimmune disease, is experimentally-modeled in the non-obese diabetic (NOD) mouse. NOD mouse studies have revealed that the so-called, diabetogenic, or disease-causing, T cells are central to the pathogenesis of T1D;yet, why these T cells are not effectively controlled via either central or peripheral mechanisms of tolerance is not fully understood. It is clear, however, that these T cells receive critical pro- and anti-proliferative signals from antigen presenting cells (APC) such as dendritic cells (DC), and that these T cell-APC interactions dramatically influence the effector T cell response to pancreatic beta cell antigens and the subsequent course of disease. Yet the molecular mechanisms underlying the control of diabetogenic T cells remain unsolved. Using a diphtheria toxin-mediated ablation model, we found that the myeloid dendritic cells (mDC) subset acts to promote T1D by priming diabetogenic T cells to pancreatic beta cell antigens in vivo. Conversely, depleting plasmacytoid DC (pDC) exacerbates the pathology- increasing both the number and severity of infiltrated islets, suggesting that, once activated, diabetogenic T cells are still under regulatory control by the pDC subset in vivo. Importantly, preliminary studies suggest a direct molecular mechanism, as the presence of intra-islet pDC correlated not only with reduced pathology but also with the localized expression of indoleamine 2,3-dioxygenase (IDO), a potent inhibitor of T cell proliferation. IDO is elicited from pDC by both type 1 and type 2 interferons (IFN). Natural Killer T (NKT) cells regulate diabetogenic CD4+ T cells in an IFN-9-dependent fashion. Using an adoptive transfer model, we found that CD4+ NKT cells are capable of regulating CD4+ diabetogenic effector T cells in vivo. This NKT cell-mediated immunoregulation occurs in the pancreas and pancreatic lymph nodes (PLN) and requires NKT cells to produce IFN-9. The apparent target of IFN-9 is host DC and not the diabetogenic T cells themselves, suggesting that the action of the NKT cells is indirect via conditioning of the host DC compartment. The most likely DC target is the pDC subset;and the most likely molecular effector is the induction of IDO. Preliminary studies suggest a causal link between NKT cells and pDC in the regulation of diabetogenic CD4+ T cells in the NOD mouse. Taken together, these findings have led us to hypothesize: (i) that NKT cells and pDC work in concert to regulate diabetogenic CD4+ T cells and modulate the tempo of insulitis in vivo;(ii) that pancreatic pDC can directly activate NKT cells to produce IFN-9;and (iii) that this IFN-9 induces pDC to in turn make IDO, which results in a localized environment that limits diabetogenic T cell proliferation. To test our hypotheses we propose the following two specific aims:
Aim 1 : To determine if pDC from the pancreas and PLN of NOD mice directly or indirectly activate NKT cells in vitro and in vivo.
Aim 2 : To determine if NKT cell-produced INF-9 and pDC-produced IDO establish a regulatory circuit that controls diabetogenic T cells in vivo.

Public Health Relevance

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease. The disease-causing, so-called diabetogenic, T cells function without normal T cell regulation. Why T cell regulation is absent or compromised in T1D is not known. We have found that certain subsets of dendritic cells can alter the function of these diabetogenic T cells. This proposal is designed to determine how these dendritic cells affect there control over diabetogenic T cells in the NOD mouse model for T1D. A better understanding of the control of the disease-causing T cells may lead to improved child health as type 1 diabetes is the most common form of autoimmunity in children in the United States.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Spain, Lisa M
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Cincinnati Children's Hospital Medical Center
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McNally, Jonathan P; Elfers, Eileen E; Terrell, Catherine E et al. (2014) Eliminating encephalitogenic T cells without undermining protective immunity. J Immunol 192:73-83
Katz, Jonathan D; Ondr, Jennifer K; Opoka, Robert J et al. (2010) Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol 185:1999-2003