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?
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.
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| 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 |
| 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 |
| 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 |
| Sada-Ovalle, Isabel; Chávez-Galán, Leslie; Torre-Bouscoulet, Luis et al. (2012) The Tim3-galectin 9 pathway induces antibacterial activity in human macrophages infected with Mycobacterium tuberculosis. J Immunol 189:5896-902 |
| Sakuishi, Kaori; Jayaraman, Pushpa; Behar, Samuel M et al. (2011) Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol 32:345-9 |
| Jayaraman, Pushpa; Sada-Ovalle, Isabel; Beladi, Sarah et al. (2010) Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med 207:2343-54 |
