The National Institute of Diabetes & Digestive & Kidney Diseases

Our research focuses on the role of dendritic cells (DCs) in T cell tolerance induction, and how these mechanisms are altered or deficient in an autoimmune setting. Specifically, we are studying DC-mediated tolerance in the NOD mouse, a model of type 1 diabetes: a human T cell-mediated organ specific autoimmune disease in which overactive T cell responses to self antigens expressed in the pancreatic islets cause destruction of insulin-producing beta cells.

Current immuno-modulatory therapies for autoimmune disease are not antigen-specific, and indiscriminately down regulate all immune responses, including those needed for responses against microbes. Therefore, it is critical to understand the induction of antigen-specific tolerance so that therapies for autoimmune disease can be designed which turn off pathogenic immune responses while leaving other essential immune responses intact.

Our goal is to harness DCs to induce autoantigen-specific tolerance. Specifically, we are interested in how dendritic cells (DCs) are involved in peripheral T cell tolerance induction in the context of autoimmunity. Below are outlined two of the areas on which we are now focusing:

Using DCs to enhance tolerance via regulatory T cells
Regulatory T cells are important inducers of dominant peripheral T cell tolerance. CD4⁺CD25⁺ regulatory T cells (T regs) have been considered “anergic”, because most types of antigen presenting cells do not stimulate T reg proliferation. However, it is now appreciated that DCs can induce proliferation and expansion of antigen-specific CD4⁺CD25⁺ T cells. We found that these DC-expanded islet-specific T regs are suppressive in vitro, and can efficiently block and reverse diabetes development, whereas polyclonal T regs from NOD mice are 100-fold less active. These results show both the importance of DCs for expanding functional T regs and the improved efficacy of antigen specific T regs in suppressing autoimmunity.
We are also now studying interactions between NOD DCs and T regs. We are interested in what signals the DCs are giving the T regs and vice versa. To do this we are using microarrays to measuring gene expression changes in these two cell types after they have been cultured together. Because DCs and T regs interact in vivo, these transcriptional changes may help us to understand how the T regs are mediating peripheral tolerance.

Use of steady state DC to enhance tolerance via anergy or deletion:
The decision between T cell immunity and tolerance is decided in part by the activation state of the DC. If antigen is presented in the context of inflammatory signals such as toll-like receptor ligands, the DC is activated and the result is immunity, but if antigens are presented to T cells in the absence of such signals, i.e. “steady state”, tolerance results. However, little is known about how this type of tolerance is altered in autoimmune individuals, and if it is possible to induce steady state tolerance in the environment of chronic autoimmune inflammation.
In order to study DC-mediated steady state tolerance in the context of autoimmunity, we are targeting an islet autoantigen directly to DCs in vivo via antibodies against endocytic recptors expressed by DCs. In vivo targeting allows one to study dendritic cell function without isolating the DCs, a process that can alter the maturation-state of the DCs.

Tarbell KV, Petit L, Zuo X, Toy P, Luo X, Mqadmi A, Yang H, Suthanthiran M, Mojsov S, Steinman RM Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med(204): 191-201, 2007. [Full Text/Abstract]

Luo X, Tarbell KV, Yang H, Pothoven K, Bailey SL, Ding R, Steinman RM, Suthanthiran M Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A(104): 2821-6, 2007. [Full Text/Abstract]

Yamazaki S, Inaba K, Tarbell KV, Steinman RM Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol Rev(212): 314-29, 2006. [Full Text/Abstract]

Yamazaki S, Patel M, Harper A, Bonito A, Fukuyama H, Pack M, Tarbell KV, Talmor M, Ravetch JV, Inaba K, Steinman RM Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc Natl Acad Sci U S A(103): 2758-63, 2006. [Full Text/Abstract]

Tarbell KV, Yamazaki S, Steinman RM The interactions of dendritic cells with antigen-specific, regulatory T cells that suppress autoimmunity. Semin Immunol(18): 93-102, 2006. [Full Text/Abstract]

Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med(199): 1467-77, 2004. [Full Text/Abstract]

Kim SK, Tarbell KV, Sanna M, Vadeboncoeur M, Warganich T, Lee M, Davis M, McDevitt HO Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells. Proc Natl Acad Sci U S A(101): 14204-9, 2004. [Full Text/Abstract]

Ranheim EA, Tarbell KV, Krogsgaard M, Mallet-Designe V, Teyton L, McDevitt HO, Weissman IL Selection of aberrant class II restricted CD8+ T cells in NOD mice expressing a glutamic acid decarboxylase (GAD)65-specific T cell receptor transgene. Autoimmunity(37): 555-67, 2004. [Full Text/Abstract]

Yamazaki S, Iyoda T, Tarbell K, Olson K, Velinzon K, Inaba K, Steinman RM Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med(198): 235-47, 2003. [Full Text/Abstract]

Tarbell KV, Lee M, Ranheim E, Chao CC, Sanna M, Kim SK, Dickie P, Teyton L, Davis M, McDevitt H CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer. J Exp Med(196): 481-92, 2002. [Full Text/Abstract]