Kristin Tarbell, Ph.D.
ISLET & AUTOIMMUNITY BRANCH
NIDDK, National Institutes of Health
Building 10-CRC, Room 5-5940
10 Center Dr.
Bethesda, MD 20892
Tel: 301-451-9360
Fax: 301-480-4515
Email: tarbellk@mail.nih.gov
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Education / Previous Training and Experience:
B.A., Cornell University, 1995
Ph.D., Stanford University, 2002
Research Statement:
Our research focuses on the role of dendritic cells (DCs) and regulatory T cells (Tregs) in peripheral T cell tolerance induction, and how these mechanisms are altered or deficient in an autoimmune setting. Dendritic cells are specialized antigen presenting cells that help determine the type of immune response that develops. Regulatory T cells are a subset of CD4 T cells that can inhibit immune responses and help induce tolerance.
Specifically, we are studying immune 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. We have also recently initiated some studies of immunomodulation in human peripheral blood cells.
Below are outlined some of the areas on which we are now focusing:
Interactions between DCs and regulatory T cells
We have shown that DCs can induce proliferation and expansion of antigen-specific CD4 CD25 regulatory T cells (T regs). 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 have used microarrays to measuring gene expression changes in these two cell types after they have been cultured together. We hypothesized that, just as conventional T cells are optimally stimulated by DCs and antigen, T regs stimulated with DCs would upregulate transcripts important for their suppressive function. Interestingly, inhibitors of the IL-1 pathway were highly upregulated in T regs stimulated by DCs. We are currently studying the role of inhibitors of IL-1 for both T reg function and induction of new T regs.
Plasmacytoid Dendritic Cells (pDCs) in NOD mice
pDCs are a rare subset of dendritic cells that produce IFN-alpha in response to innate immune signals, but can also present antigen like conventional DCs. Published reports on the role of pDCs in autoimmunity are mixed. IFN-alpha production can be pro-inflammatory, yet pDCs can also play a tolerogenic role by, for example, inducing Tregs. We are now measuring pDC function in NOD mice compared to control strains.
Use of steady state DC to enhance tolerance via anergy or deletion:
If antigen is presented in the context of inflammatory signals such as toll-like receptor ligands, DCs can be 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 islet autoantigens 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.
Lab Group
Tarbell lab group fall 2008. From left Annie Lau, Stephanie Dorta, Jeff Price, Kristin Tarbell, Amelia Keaton , Angel Li, Geetanjali Bansal
Selected Publications:
1) Y. Belkaid and K.V.Tarbell, Arming Treg Cells at the Inflammatory Site, Immunity 2009, V30, p322-323.
2) Y. Belkaid and K. Tarbell, Regulatory T cells in the Control of Host-Microorganism Interactions, Ann. Rev. Immunol. 2009 Vol. 27: 551-589.
3) A. Mukhopadhaya, T. Hanafusa, I. Jarchum, Y. Chen, Y Iwai, D.V. Serreze, R. M. Steinman, K. V. Tarbell, and T. P. DiLorenzo. Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 T cells in NOD mice. Proc Natl Acad Sci U S A. 2008. V105 p6374-6379.
4) X. Luo*, K. V. Tarbell*, H. Yang, K. Pothoven, S. L. Bailey, R. Ding, R. M. Steinman and M. Suthanthiran. Dendritic cells with TGF-β1 differentiate naïve CD4 CD25- T cells into islet-protective Foxp3 regulatory T cells * equal authorship. Proc Natl Acad Sci. USA 2007 Feb 20; 104(8): 2821-6.
5) K. V. Tarbell, L. Petit, X. Zuo, P. Toy, X. Luo, A. Mqadmi, S. Yamazaki, S. Mojsov, R. M. Steinman. Dendritic cell-expanded, islet-specific, CD4 CD25 CD62L regulatory T cell restore normoglycemia in diabetic NOD mice. J. Exp. Med. 2007 204: 191–201.
6) S.Yamazaki , K. Inaba, K. V.Tarbell, R. M. Steinman. Dendritic cells expand antigen-specific Foxp3 CD25 CD4 regulatory T cells, including suppressors of alloreactivity. Immunol. Rev. 2006 Aug; 212:314-329.
7) K.V. Tarbell, S. Yamazaki , R. M. Steinman. The interactions of dendritic cells with antigen-specific, regulatory T cells that suppress autoimmunity. Semin. Immunol. 2006 Apr;18(2):93-102.
8) S. Yamazaki, M. Patel, A. Harper, A. Bonito, H. Fukuyama, M. Pack, K.V. Tarbell, M. Talmor, J.V. Ravetch, K. Inaba, R.M. Steinman. 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. 2006 Feb 21;103(8): 2758-63.
9) E. L. Masteller, M.R. Warner, Q. Tang, K.V. Tarbell, H. McDevitt, J.A. Bluestone. Expansion of functional endogenous antigen-specific CD4 CD25 regulatory T cells from nonobese diabetic mice. J Immunol. 2005 Sep 1;175(5):3053-9.
10) E. A. Ranheim, K. V. Tarbell, M. Krogsgaard, V. Mallet-Designe, L. Teyton, H.O. McDevitt, and I. L. Weissman. Selection and Function of Aberrant Class II Restricted CD8 T Cells in NOD Mice Expressing a Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgene. Autoimmunity. 2004 Dec;37(8):555-67.
11) S. Kim*, K. V. Tarbell*, M. Sanna, M. Vadeboncoeur, T. Warganich, M. Lee, M. Davis and H. O. McDevitt. Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14204-9. * equal authorship.
12) K. V Tarbell, S. Yamazaki, K. Olson, P. Toy, R. M. Steinman. CD25 CD4 T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J. Exp. Med. 2004 199: 1467-1477.
13) S. Yamazaki, T. Iyoda, K. Tarbell, K. Olson, K. Velinzon, K. Inaba, and R. M. Steinman. Direct Expansion of Functional CD25 CD4 Regulatory T Cells by Antigen-processing Dendritic Cells. 2003 J. Exp. Med.,198: 235 - 247.
14) K. V. Tarbell, M. Lee, E. Ranheim, C. C. Chao, M. Sanna, S. Kim, P. Dickie, L. Teyton, M. Davis, and H. O. McDevitt. 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., Aug 2002; 196: 481 - 492.
15) S. Hsieh, N. Chen, K. Tarbell, N. Liao, Y. Lai, K. Lee, K. Lee, S. Wu, H. Sytwu, S. Han, and H. McDevitt. Transgenic Mice Expressing Surface Markers for IFNγ and IL-4 producing Cells Molecular Immunology. 37 (2000) 281-293.
Page last updated: March 25, 2009
