Significance: The continuing HIV/AIDS epidemic and the spread of multi-drug resistant Mycobacterium tuberculosis (Mtb) has perpetuated an epidemic of tuberculosis in populations around the world. While BCG is used universally as a vaccine, it is not effective in preventing pulmonary tuberculosis. To combat this ongoing worldwide scourge, vaccine development for tuberculosis is a priority. Convincing experimental evidence exists that CD8+ T cells are required for optimal immunity to tuberculosis in mice and other experimental animals. Whether vaccine strategies can be developed to elicit protective CD8+ T cells remains to be determined. Innovation: We have developed experimental strategies to elucidate the molecular basis for how CD8+ T cells mediate protection. We will measure the effector functions expressed by effector and memory M. tuberculosis-specific CD8+ T cells at the single cell level to determine how CD8+ T cells mediate protection. We will learn how the CD8+ T cell response evolves during chronic infection and which effector functions are expressed at different phases of infection. By correlating the genetic fingerprint atthe single cell level with the protective functions of M. tuberculosis-specific CD8+ T cells, we wil develop a 'signature' that can identify vaccine strategies that elicit protection.
Aims : First, we will determine how the function of primary effector vs. memory CD8+ T cells differs during M. tuberculosis infection. We hypothesize that heterogeneity in the coordinated expression of 'killer genes' limits the number of competent CTL early during the response to M. tuberculosis and impairs host protection. TB10.4 is the immunodominant antigen recognized by CD8+ T cells in the lungs of infected C57BL/6 mice. We will determine the gene expression profile at the single cell level to determine how heterogeneity among TB10.4-specific CD8+ T cells evolves and affects immunity to M. tuberculosis. We hypothesize that memory CD8+ T cells will be more efficient CTL and mediate better protection against M. tuberculosis. Using both in vivo and in vitro models, we will determine how the expression and distribution of effector molecules affects the control of intracellular M. tuberculosis by primary effector and memory CD8+ T cells. In the 2nd aim, we will determine whether the gene expression pattern and distribution of memory CD8+ T cells elicited by vaccination correlates with protection against M. tuberculosis. We hypothesize that vaccination not only alters the number of antigen-specific T cells, but also induces a gene expression program. By measuring the protection conferred by each vaccine, we will correlate protection with changes in the CD8+ T cell function and the distribution of gene expression. Summary: Our in vitro and in vivo models will allow us to better define the mechanisms used by CD8+ T cells to restrict bacterial replication. By elucidating the molecular mechanisms used by CD8+ T cells to restrict M. tuberculosis infection, we expect that this approach will be an important advance in the rational development of vaccines.

Public Health Relevance

Pulmonary tuberculosis, the disease caused by Mycobacterium tuberculosis, is a threat to global health. Infection is usually asymptomatic because the immune system is able to limit bacterial growth. The disease tuberculosis occurs when the immune system is no longer able to contain the infection. This research application seeks understand how T cells mediate protection to tuberculosis. In particular, we will define a genetic signature of protective CD8+ T cells that respond to tuberculosis. In addition, using the same approach, the genetic signature of different vaccine strategies will be determined and correlated with their ability to generate protective immunity. It is hoped that by defining feature of host resistance, we can apply this information to the development of biomarkers that are associated with successful vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI067731-06A1
Application #
8476811
Study Section
Special Emphasis Panel (ZRG1-IDM-V (02))
Program Officer
Parker, Tina M
Project Start
2005-12-15
Project End
2013-09-30
Budget Start
2012-06-15
Budget End
2013-09-30
Support Year
6
Fiscal Year
2012
Total Cost
$506,783
Indirect Cost
$186,759
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Behar, Samuel M; Carpenter, Stephen M; Booty, Matthew G et al. (2014) Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus. Semin Immunol 26:559-77
Nobrega, Claudia; Nunes-Alves, Claudio; Cerqueira-Rodrigues, Bruno et al. (2013) T cells home to the thymus and control infection. J Immunol 190:1646-58
Woodworth, Joshua S; Shin, Daniel; Volman, Mattijs et al. (2011) Mycobacterium tuberculosis directs immunofocusing of CD8+ T cell responses despite vaccination. J Immunol 186:1627-37
Behar, Samuel M; Martin, Constance J; Nunes-Alves, Cláudio et al. (2011) Lipids, apoptosis, and cross-presentation: links in the chain of host defense against Mycobacterium tuberculosis. Microbes Infect 13:749-56