Role of gamma/delta T cells in Vaccine Induced Immunity

Summary

Principal Investigator: DANIEL HOFT
Affiliation: Saint Louis University
Country: USA
Abstract: A subset of human T cells express T cell receptors (TCR) composed of gamma and delta subunits, homologous to alpha and beta proteins but encoded by distinct gene segments. The rapid response of gamma/delta T cells to microbial epithelial invasion suggests they represent a first line of defense for innate immunity. Others have shown that gamma/delta T cells provide a link between innate and adaptive immunity, producing cytokines such as IFN-gamma important for inducing type 1 immunity. We have identified a more direct adaptive immune role for gamma/delta T cells. We found that BCG vaccination induces human gamma/delta memory T cells characterized by more rapid and potent secondary responses. Vaccination with canarypox vectors and vaccinia also induced human gamma/delta memory T cell responses. The major focus of this RO1 has been to determine whether these memory gamma/delta T cell responses provide important helper and/or effector functions involved in protective immunity, and we have produced evidence for both. This competing continuation application will further investigate the following 3 hypotheses: #1) Mycobacteria- and poxviral-specific gamma/delta T cells have unique antigen specificities and can be used as bioindicators to identify pathogen derived stimulatory antigens, #2) Human gamma/delta T cells specific for mycobacterial and poxviral antigens can provide helper functions for the development of optimal memory immune alpha/beta T cell responses, and #3) Human gamma/delta T cells specific for mycobacteria and poxviruses can provide direct effector functions capable of inhibiting the replication of these intracellular pathogens. Studies of smallpox-specific gamma/delta T cell immunity, detailed TCR spectratyping comparisons between gamma/delta T cells induced by these different pathogens/vectors, identification of the pathogenic-specific antigenic molecules inducing these responses, and detailed studies of the mechanisms involved in gamma/delta T cell helper and effector immune functions are major additions in this application cycle. In addition, Aims 2 & 3 will specifically address in detail the antigen specificity of gamma/delta T cell responses. Another major addition is the inclusion of a subcontract to Dr. Dobos at Colorado State, who will pursue detailed biochemical studies designed to identify the specific components of mycobacteria and vaccinia that induce gamma/delta T cells relevant for vaccine development.
Funding Period: 2000-07-01 - 2012-02-28
more information: NIH RePORT

Top Publications

  1. pmc Granzyme A produced by γ(9)δ(2) T cells induces human macrophages to inhibit growth of an intracellular pathogen
    Charles T Spencer
    Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University, St Louis, Missouri, USA
    PLoS Pathog 9:e1003119. 2013
  2. pmc CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responses
    Steven M Truscott
    Department of Internal Medicine, Division of Immunobiology, Saint Louis University, St Louis, MO 63104, USA
    Infect Immun 78:5295-306. 2010
  3. pmc Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding
    Jidong Zhang
    Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA
    J Immunol 186:5885-95. 2011
  4. pmc Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children
    Daniel F Hoft
    Department of Internal Medicine, Saint Louis University Vaccine and Treatment Evaluation Unit, Missouri, USA
    J Infect Dis 204:845-53. 2011
  5. ncbi Flow-cytometric detection of vaccinia-induced memory effector CD4(+), CD8(+), and gamma delta TCR(+) T cells capable of antigen-specific expansion and effector functions
    Getahun Abate
    Department of Internal Medicine, Saint Louis University, St Louis, Missouri 63110, USA
    J Infect Dis 192:1362-71. 2005
  6. pmc Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies
    S de Valliere
    Department of Internal Medicine, Saint Louis University Health Science Center, MO 63110, USA
    Infect Immun 73:6711-20. 2005
  7. pmc Only a subset of phosphoantigen-responsive gamma9delta2 T cells mediate protective tuberculosis immunity
    Charles T Spencer
    Department of Internal Medicine, Saint Louis University, St Louis, MO 63104, USA
    J Immunol 181:4471-84. 2008
  8. pmc A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers
    Daniel F Hoft
    Department of Internal Medicine and Molecular Biology, Saint Louis University Medical Center, and Center for Vaccine Development, Saint Louis, MO 63104, USA
    J Infect Dis 198:1491-501. 2008

Scientific Experts

  • DANIEL HOFT
  • Getahun Abate
  • Charles T Spencer
  • Steven M Truscott
  • Christopher S Eickhoff
  • Jidong Zhang
  • Azra Blazevic
  • S de Valliere
  • Isaac G Sakala
  • Christopher J Froelich
  • Rebecca Linn
  • Mei Xia
  • Sunil S Metkar
  • Guangyong Peng
  • Jianguo Liu
  • Huan Ning
  • Xuesong Qian
  • Jeffrey D Price
  • John P Atkinson
  • Claudia Kemper
  • Joy Eslick
  • A Blazevic
  • Thomas P Monath
  • Frances K Newman
  • Robert B Belshe
  • Sharon E Frey
  • G Abate
  • R M Heuertz

Detail Information

Publications9

  1. pmc Granzyme A produced by γ(9)δ(2) T cells induces human macrophages to inhibit growth of an intracellular pathogen
    Charles T Spencer
    Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University, St Louis, Missouri, USA
    PLoS Pathog 9:e1003119. 2013
    ..This pathway may provide a protective mechanism relevant for the development of new vaccines and/or immunotherapies for macrophage-resident chronic microbial infections...
  2. pmc CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responses
    Steven M Truscott
    Department of Internal Medicine, Division of Immunobiology, Saint Louis University, St Louis, MO 63104, USA
    Infect Immun 78:5295-306. 2010
    ..Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines...
  3. pmc Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding
    Jidong Zhang
    Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA
    J Immunol 186:5885-95. 2011
    ..Strategies designed to tip the balance toward positive regulation of p28 induction by mycobacteria could lead to enhanced protective tuberculosis immunity...
  4. pmc Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children
    Daniel F Hoft
    Department of Internal Medicine, Saint Louis University Vaccine and Treatment Evaluation Unit, Missouri, USA
    J Infect Dis 204:845-53. 2011
    ..However, whether combinations of LAIV and TIV are safe and equally immunogenic is unknown. Furthermore, LAIV is more protective than TIV in children for unclear reasons...
  5. ncbi Flow-cytometric detection of vaccinia-induced memory effector CD4(+), CD8(+), and gamma delta TCR(+) T cells capable of antigen-specific expansion and effector functions
    Getahun Abate
    Department of Internal Medicine, Saint Louis University, St Louis, Missouri 63110, USA
    J Infect Dis 192:1362-71. 2005
    ..CFSE-based flow-cytometric assays will be useful in evaluating cell-mediated immune responses induced by new smallpox vaccines...
  6. pmc Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies
    S de Valliere
    Department of Internal Medicine, Saint Louis University Health Science Center, MO 63110, USA
    Infect Immun 73:6711-20. 2005
    ..We conclude that mycobacterium-specific antibodies are capable of enhancing both innate and cell-mediated immune responses to mycobacteria...
  7. pmc Only a subset of phosphoantigen-responsive gamma9delta2 T cells mediate protective tuberculosis immunity
    Charles T Spencer
    Department of Internal Medicine, Saint Louis University, St Louis, MO 63104, USA
    J Immunol 181:4471-84. 2008
    ..Specific targeting of protective gamma(9)delta(2) T cell subsets will be important for future tuberculosis vaccines...
  8. pmc A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers
    Daniel F Hoft
    Department of Internal Medicine and Molecular Biology, Saint Louis University Medical Center, and Center for Vaccine Development, Saint Louis, MO 63104, USA
    J Infect Dis 198:1491-501. 2008
    ..rBCG30, which overexpresses the Mycobacterium tuberculosis secreted antigen Ag85b, was the first rBCG shown to induce significantly greater protection against TB in animals than parental BCG...