Identifying Ligands with Soluble Gamma/Delta TCRs

Summary

Principal Investigator: REBECCA L O'BRIEN
Abstract: Although the gammadelta T cells have been shown to have immunoregulatory effects in a number of experimental systems, their role in immunobiology is still not clear. Surprisingly, it is possible to divide gammadelta T cells into functional subsets based on the Vgamma and/or Vdelta elements they express. Based on such findings, we have hypothesized that certain inducible host molecules act as ligands for gammadelta T cell receptors (TCRs), and are important in eliciting their immunoregulatory effects. However, the nature of the ligands recognized by gammadelta TCRs remains controversial. Furthermore, recent findings have suggested that gammadelta T cell responses can be evoked by molecules other than the TCR, such as chemokine receptors or the Toll-like receptors of the innate immune system, making experiments in which cellular activation is used as a readout for TCR-mediated stimulation difficult to interpret. We believe that the gammadelta T cell receptor itself may hold the key to elucidating the role of the TCR in bringing about gammadelta T cell function. In this proposal, we present preliminary evidence that multimerized versions of mouse soluble gammadelta TCRs can be used like monoclonal antibodies to stain cells bearing their putative ligands. The specific aims of this proposal make use of such soluble TCRs to further investigate the natural ligands of gammadelta TCRs: Aim 1 - to investigate properties of natural ligands for gammadelta TCRs. Using labeled versions of four different gammadelta soluble TCRs (sTCRs), we will use flow cytometry in an attempt to detect the ligands in thymus and certain peripheral organs that drive the development or differentiation of distinct gammadelta T cell subsets. Second, using sTCRs from a subset whose TCRs are variable, we will determine whether different members of a given subset can recognize the same ligand. Third, we will attempt to determine if these ligands are MHC class I or class I-like by examining cells from particular mutant mouse strains. Aim 2 - to purify and identify natural ligands for gammadelta TCRs. Using two different approaches, we will attempt to isolate and identify the natural ligand for the V?6/Vd1 invariant TCR, as well as for a typical polymorphic Vgamma1/Vdelta6.3 TCR. The first approach involves screening cDNA expression clones for their ability to stain with either the Vgamma6/Vdelta1 or Vgamma1/Vdelta6.3 sTCR. The backup approach involves generation of ligand specific mAbs, identified by their ability to block sTCR/ligand binding, as reagents to affinity-purify the ligand.
Funding Period: 2005-07-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Analysis of gamma delta T cell functions in the mouse
    Willi K Born
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    J Immunol 184:4055-61. 2010
  2. ncbi Balanced approach of gammadelta T cells to type 2 immunity
    Willi K Born
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    Immunol Cell Biol 88:269-74. 2010
  3. pmc The influence of IgE-enhancing and IgE-suppressive gammadelta T cells changes with exposure to inhaled ovalbumin
    Yafei Huang
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    J Immunol 183:849-55. 2009
  4. pmc Allergic airway hyperresponsiveness-enhancing gammadelta T cells develop in normal untreated mice and fail to produce IL-4/13, unlike Th2 and NKT cells
    Niyun Jin
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    J Immunol 182:2002-10. 2009
  5. pmc Evidence that CD8+ dendritic cells enable the development of gammadelta T cells that modulate airway hyperresponsiveness
    Laura Cook
    Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA
    J Immunol 181:309-19. 2008
  6. pmc Role of two distinct gammadelta T cell subsets during West Nile virus infection
    Thomas Welte
    Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA
    FEMS Immunol Med Microbiol 53:275-83. 2008
  7. pmc Macrophages express multiple ligands for gammadelta TCRs
    M Kemal Aydintug
    Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, United States
    Mol Immunol 45:3253-63. 2008
  8. ncbi Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells
    Niyun Jin
    Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA
    J Immunol 179:2961-8. 2007
  9. ncbi Regulatory role of gammadelta T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis
    Philip L Simonian
    Department of Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
    J Immunol 177:4436-43. 2006
  10. ncbi The function of gammadelta T cells in innate immunity
    Willi K Born
    Department of Immunology, at National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA
    Curr Opin Immunol 18:31-8. 2006

Scientific Experts

  • W K Born
  • REBECCA L O'BRIEN
  • Niyun Jin
  • Christina L Roark
  • M Kemal Aydintug
  • Yafei Huang
  • J M Wands
  • Nobuaki Miyahara
  • Erwin W Gelfand
  • Christian Taube
  • Thomas Welte
  • Laura Cook
  • Philip L Simonian
  • Youn Soo Hahn
  • Hua Huang
  • Terry A Potter
  • John F Anderson
  • Tian Wang
  • Jacquelyn Lamb
  • Jennifer L Chain
  • Laurent Gapin
  • Jennifer L Matsuda
  • Jena D French
  • Fernando Diaz del Valle
  • Brent E Palmer
  • Koichi Ikuta
  • Ivor S Douglas
  • Andrew P Fontenot

Detail Information

Publications10

  1. ncbi Analysis of gamma delta T cell functions in the mouse
    Willi K Born
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    J Immunol 184:4055-61. 2010
    ..They also are revealed as a potentially useful target for immune intervention...
  2. ncbi Balanced approach of gammadelta T cells to type 2 immunity
    Willi K Born
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    Immunol Cell Biol 88:269-74. 2010
    ..However, after airway allergen exposure, suppressive gammadelta T cells become dominant. The underlying mechanisms are discussed...
  3. pmc The influence of IgE-enhancing and IgE-suppressive gammadelta T cells changes with exposure to inhaled ovalbumin
    Yafei Huang
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    J Immunol 183:849-55. 2009
    ..Thus, airway allergen challenge differentially affects two distinct subsets of gammadelta T cells with nonoverlapping functional potentials, and the outcome is IgE suppression...
  4. pmc Allergic airway hyperresponsiveness-enhancing gammadelta T cells develop in normal untreated mice and fail to produce IL-4/13, unlike Th2 and NKT cells
    Niyun Jin
    Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
    J Immunol 182:2002-10. 2009
    ..We conclude that both the development and the cytokine potential of the AHR-enhancing gammadelta T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR...
  5. pmc Evidence that CD8+ dendritic cells enable the development of gammadelta T cells that modulate airway hyperresponsiveness
    Laura Cook
    Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA
    J Immunol 181:309-19. 2008
    ..Our findings suggest that CD8+ DCs in the lymphoid tissues enable an early step in the development of gammadelta T cells through direct cell contact. DC-expressed CD8 might take part in this interaction...
  6. pmc Role of two distinct gammadelta T cell subsets during West Nile virus infection
    Thomas Welte
    Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA
    FEMS Immunol Med Microbiol 53:275-83. 2008
    ..These results suggest that Vgamma1(+) and Vgamma4(+) cells play distinct roles in protection and pathogenesis during WNV infection...
  7. pmc Macrophages express multiple ligands for gammadelta TCRs
    M Kemal Aydintug
    Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, United States
    Mol Immunol 45:3253-63. 2008
    ....
  8. ncbi Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells
    Niyun Jin
    Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA
    J Immunol 179:2961-8. 2007
    ..The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses...
  9. ncbi Regulatory role of gammadelta T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis
    Philip L Simonian
    Department of Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
    J Immunol 177:4436-43. 2006
    ..These findings indicate that chronic inhalation of B. subtilis can result in T cell accumulation in the lung and fibrosis, constituting a new model of immune-mediated pulmonary fibrosis...
  10. ncbi The function of gammadelta T cells in innate immunity
    Willi K Born
    Department of Immunology, at National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA
    Curr Opin Immunol 18:31-8. 2006
    ..Thus, at present, much evidence suggests that gammadelta T cells function in an innate manner, although they are arguably the most complex and advanced cellular representatives of the innate immune system...