Immunity to microbial pathogens involves numerous checks and balances that are regulated by multiple pathways. This application addresses the novel and potentially critical role that Tim3, a member of the T cell Immunoglobulin and Mucin domain family of proteins, plays in the defense against tuberculosis. Tim3 is emerging as an important regulator of both adaptive and innate immunity, and is conserved between humans and mice. However, the role of Tim3 in modulating immunity to bacterial pathogens has not been examined. While signaling via Tim3 on TH1 cells has been purported to deliver a negative signal that could reduce unintended tissue inflammation, the consequence of Tim3 binding to its ligand on participating antigen-presenting cells is unclear. We have discovered that Tim3 binding to its ligand, Galectin-9 (Gal9) stimulates antibactericidal activity in innate cells both in vivo and in vitro. Tim3 engagement of Gal9 expressed by Mtb infected macrophages induces caspase-1 dependent IL-12 secretion and restricts intracellular bacterial replication. We also find that Tim3-expressing CD4+ and CD8+ T cells accumulate in the lungs of mice infected with virulent M. tuberculosis (Mtb). If, as has been reported for human T cells during chronic viral infection, Tim3-signaling leads to T cell dysfunction and apoptosis, we hypothesize that interactions between Tim3+ T cells in the lung and Gal9 expressing macrophages leads to T cell exhaustion and impairs anti-mycobacterial immunity. Thus, it appears that Tim3 and Gal9 are central players in a bidirectional regulatory circuit that modulates antimicrobial TH1 responses. In the case of acute infection, this circuit could be an important mechanism that limits tissue damage and immunopathology from an overly exuberant immune response, while simultaneously activating innate immunity against microbial pathogens. On the other hand, such a mechanism may be detrimental during chronic infection and lead to suboptimal immunity because of premature clonal contraction or T cell exhaustion. These studies have implications beyond providing a better understanding of immunity to tuberculosis. Our data establish a novel paradigm for how cross-talk between the adaptive and innate immune system occurs. Therefore, the studies proposed below will address a potentially critical, but as yet underappreciated immunological pathway, that affects immunity to tuberculosis and possibility other pathogens as well.
Our aims are:
7 Aim 1. How does Tim3/Gal9 activate MX, stimulate innate immunity, and lead to killing of intracellular Mtb? 7 Aim 2. Does IL-1 and its downstream mediators activate human MX to kill Mtb? 7 Aim 3. How does the Tim3/Gal9 interaction modulate immunity to tuberculosis in vivo?

Public Health Relevance

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis, is a threat to global health. The disease tuberculosis occurs when the immune system is no longer able to contain the infection. This research proposal seeks to discover new ways that cells of the immune system kill bacteria. It is hoped that by understanding these features of host resistance, new strategies can be developed for the treatment of tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085669-03
Application #
8301804
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Parker, Tina M
Project Start
2010-07-01
Project End
2013-03-31
Budget Start
2012-07-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$514,621
Indirect Cost
$198,735
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
Nunes-Alves, Cláudio; Booty, Matthew G; Carpenter, Stephen M et al. (2014) In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol 12:289-99
Jayaraman, Pushpa; Sada-Ovalle, Isabel; Nishimura, Tomoyasu et al. (2013) IL-1? promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation. J Immunol 190:4196-204
Sakuishi, Kaori; Jayaraman, Pushpa; Behar, Samuel M et al. (2011) Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol 32:345-9