T cell recognition of antigenic self-TCR sequences constitutes a distinct peripheral autoregulatory mechanism for limiting inflammatory reactions mediated by Th1 cells directed at tissue-specific antigens such as myelin proteins. Data obtained from our clinical trials using TCR peptides to vaccinate patients with multiple sclerosis (MS) have raised crucial questions regarding the origin and mechanism of action of TCR- specific T cells that will require a return to animal models. Specifically, we have observed that TCR-reactive T cells may acquire properties associated with CD4+CD25+ regulatory T cells (Treg), in addition to their previously documented ability to regulate Th1 cells through the release of IL-10, with properties similar to Th2 or Tr1 cells. These observations raise the fundamental question of whether the TCR-reactive cells represent a single distinct regulatory lineage or whether T cells bearing T cell receptors specific for self TCR determinants can differentiate into different types of regulatory or effector T cells according to their micro- environment. This question has important implications because in the latter case, the autoimmune disease process itself might direct a different distribution of TCR-reactive T cell subtypes than occurs during health, with unknown effects on regulatory function. We thus propose the hypothesis that TCR-specific T cells represent a unique lineage of autoreactive cells that mediate a spectrum of regulatory effects that are dependent on both thymic and peripheral differentiation pathways. To address this hypothesis, we propose to: 1) Determine what are the developmental pathways for CD4+ TCR-specific T cells;2) Determine what are the governing mechanisms by which TCR-reactive T cells inhibit pathogenic and bystander T cells and prevent experimental autoimmune encephalomyelitis (EAE);and 3) Evaluate the spectrum of TCR-reactive T cell types in HC and in MS patients before and after vaccination and their effects on immune function. We will utilize humanized Tg mice that express HLA-DR2, a known risk factor for MS, that are highly susceptible to EAE induced with myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide. Moreover, in order to more effectively follow pathogenic T cells and evaluate induction of a focused anti-TCR response, we will utilize DR2 mice that also express a human TCR specific for myelin basic protein (MBP)-85-99 peptide. These DR2/TCR+ mice are highly susceptible to EAE induced with the MBP-85-99 peptide, and we further propose to mimic human T cell presentation of self-TCR determinants by producing DR2/CIITA-Tg mice, in which T cells are programmed to over-express class II molecules. Studies in these mice and in mice deficient in the Treg associated Foxp3 gene are crucial for a definitive determination of differences in the protective function of various TCR-reactive subtypes. Results from the animal models will then be translated back to human donors to evaluate the distribution of TCR subtypes present in un-immunized HC and TCR vaccinated MS patients to establish predominant patterns that are associated with clinical benefit.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
Buenafe, Abigail C; Andrew, Shayne; Offner, Halina et al. (2012) Regulatory T cells play a role in T-cell receptor CDR2 peptide regulation of experimental autoimmune encephalomyelitis. Immunology 135:168-79
Buenafe, Abigail C; Andrew, Shayne; Afentoulis, Michael et al. (2010) Prevention and treatment of experimental autoimmune encephalomyelitis with clonotypic CDR3 peptides: CD4(+) Foxp3(+) T-regulatory cells suppress interleukin-2-dependent expansion of myelin basic protein-specific T cells. Immunology 130:114-24
Wang, Chunhe; Dehghani, Babak; Li, Yuexin et al. (2009) Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1. Immunology 126:329-35
Vandenbark, Arthur A; Offner, Halina (2008) Critical evaluation of regulatory T cells in autoimmunity: are the most potent regulatory specificities being ignored? Immunology 125:1-13
Vandenbark, Arthur A; Abulafia-Lapid, Rivka (2008) Autologous T-cell vaccination for multiple sclerosis: a perspective on progress. BioDrugs 22:265-73
Sinha, Sushmita; Kaler, Laurie J; Proctor, Thomas M et al. (2008) IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis. J Immunol 180:2679-85
Vandenbark, Arthur A; Culbertson, Nicole E; Bartholomew, Richard M et al. (2008) Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology 123:66-78
Imam, Sarah A; Guyton, Mary K; Haque, Azizul et al. (2007) Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients. J Neuroimmunol 190:139-45
Subramanian, Sandhya; Tovey, Micah; Afentoulis, Michael et al. (2005) Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta. Clin Immunol 115:162-72
Huan, Jianya; Culbertson, Nicole; Spencer, Leslie et al. (2005) Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res 81:45-52

Showing the most recent 10 out of 136 publications