Type 1 diabetes (T1 D) is a tissue specific autoimmune disease characterized by the T mediated destruction of the insulin producing b cells of the islets of Langerhans. Treatment of diabetes has focused on the use of insulin replacement. However, this treatment can be difficult to regulate and has many shortcomings. While the surgical techniques for transplanting pancreatic islets is now at hand, problems remain. First and foremost is that fact that even syngeneic grafts are rejected due to the same autoimmune mechanisms that caused the initial islet cell loss. This process must be controlled to promote effective transplant function. Heretofore, most of the efforts in understanding the pathogenesis and treatment of T1D have focused on the role of CD4+ T cells. In this proposal we expand the current ideas of immunoregulation to CD8+ cells in T1D. We seek to study the repertoire and regulation of b cell specific CD8+ T cells, the role of CD8+ T cell subset, Tcl and Tc2 on regulation, and the roles of cytokines produced by CD4+ T cells in shaping the CD8+ T cell response. This will be accomplished by combing the use of MHC class I tetramers, peptides and novel immunization strategies. We will then use this information to deviate or anergize/delete peptide specific T cells and control the critical CD8+ T cell response in T1D to allow effective islet cell transplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunobiology Study Section (IMB)
Program Officer
Esch, Thomas R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Whitfield-Larry, Fatima; Young, Ellen F; Talmage, Garrick et al. (2011) HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/ýýc(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. Diabetes 60:1726-33
Vincent, Benjamin G; Young, Ellen F; Buntzman, Adam S et al. (2010) Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice. J Immunol 184:4196-204
Li, Chengwen; Goudy, Kevin; Hirsch, Matt et al. (2009) Cellular immune response to cryptic epitopes during therapeutic gene transfer. Proc Natl Acad Sci U S A 106:10770-4
Young, Ellen F; Hess, Paul R; Arnold, Larry W et al. (2009) Islet lymphocyte subsets in male and female NOD mice are qualitatively similar but quantitatively distinct. Autoimmunity 42:678-91
Frelinger, Jeffrey A (2008) Novel epitope begets a novel pathway in type 1 diabetes progression. J Clin Invest 118:3268-71
Wong, Carmen P; Stevens, Rosemary; Long, Brian et al. (2007) Identical beta cell-specific CD8(+) T cell clonotypes typically reside in both peripheral blood lymphocyte and pancreatic islets. J Immunol 178:1388-95
Maile, Robert; Pop, Shannon M; Tisch, Roland et al. (2006) Low-avidity CD8lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8hi T cell responses to the same antigen. Eur J Immunol 36:397-410
Long, Brian; Wong, Carmen P; Wang, Yaming et al. (2006) Lymphopenia-driven CD8(+) T cells are resistant to antigen-induced tolerance in NOD.scid mice. Eur J Immunol 36:2003-12
Wong, Carmen P; Li, Li; Frelinger, Jeffrey A et al. (2006) Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8+ T cells in diabetic nonobese diabetic mice. J Immunol 176:1637-44
Maile, Robert; Siler, Catherine A; Kerry, Samantha E et al. (2005) Peripheral ""CD8 tuning"" dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo. J Immunol 174:619-27

Showing the most recent 10 out of 11 publications