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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048391-07
Application #
7772305
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Parker, Tina M
Project Start
2000-07-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2010
Total Cost
$356,913
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Abate, Getahun; Spencer, Charles T; Hamzabegovic, Fahreta et al. (2015) Mycobacterium-Specific ?9?2 T Cells Mediate Both Pathogen-Inhibitory and CD40 Ligand-Dependent Antigen Presentation Effects Important for Tuberculosis Immunity. Infect Immun 84:580-9
Sakala, Isaac G; Kjer-Nielsen, Lars; Eickhoff, Christopher S et al. (2015) Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites. J Immunol 195:587-601
Spencer, Charles T; Abate, Getahun; Sakala, Isaac G et al. (2013) Granzyme A produced by ?(9)?(2) T cells induces human macrophages to inhibit growth of an intracellular pathogen. PLoS Pathog 9:e1003119
Hoft, Daniel F; Babusis, Elizabeth; Worku, Shewangizaw et al. (2011) Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis 204:845-53
Zhang, Jidong; Qian, Xuesong; Ning, Huan et al. (2011) Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding. J Immunol 186:5885-95
Truscott, Steven M; Abate, Getahun; Price, Jeffrey D et al. (2010) CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responses. Infect Immun 78:5295-306
Spencer, Charles T; Abate, Getahun; Blazevic, Azra et al. (2008) Only a subset of phosphoantigen-responsive gamma9delta2 T cells mediate protective tuberculosis immunity. J Immunol 181:4471-84
Hanekom, Willem A; Dockrell, Hazel M; Ottenhoff, Tom H M et al. (2008) Immunological outcomes of new tuberculosis vaccine trials: WHO panel recommendations. PLoS Med 5:e145
Hoft, Daniel F; Blazevic, Azra; Abate, Getahun et al. (2008) A new recombinant bacille Calmette-Guerin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. J Infect Dis 198:1491-501
de Valliere, S; Abate, G; Blazevic, A et al. (2005) Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies. Infect Immun 73:6711-20

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