Genomes and Genes
Role of gamma/delta T cells in Vaccine Induced Immunity
Principal Investigator: DANIEL HOFT
Affiliation: Saint Louis University
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
- Granzyme A produced by γ(9)δ(2) T cells induces human macrophages to inhibit growth of an intracellular pathogenCharles 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...
- CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responsesSteven 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...
- Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 bindingJidong 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...
- Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young childrenDaniel 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...
- Flow-cytometric detection of vaccinia-induced memory effector CD4(+), CD8(+), and gamma delta TCR(+) T cells capable of antigen-specific expansion and effector functionsGetahun 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...
- Enhancement of innate and cell-mediated immunity by antimycobacterial antibodiesS 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...
- Only a subset of phosphoantigen-responsive gamma9delta2 T cells mediate protective tuberculosis immunityCharles 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...
- A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteersDaniel 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...