The protective immune response operative in tuberculous infection is not completely defined. Nevertheless, it is generally accepted that Thi-mediated immunity plays a significant role in engendering protection against M. tuberculosis. This notion is perhaps best supported by the fact that HI V-infected individuals, in whom Thi cell apoptosis occurs, are highly susceptible to the tubercie bacillus. Emerging evidence suggests that apoptosis of T cells, including the Thi subtype. occurs during tuberculous infection. Our laboratory has recently observed that Th1 and Th2 cells can be differentially modulated to undergo apoptosis. We previously reported that CD95-meidated apoptosis in response to CD3/TCR (T cell receptor complex) ligation is observed only in Thi, and not in Th2 T cell clones. In contrast to Th2 lymphocytes, Thi cells demonstrated a distinct requirement for costimulation via ligation of specific T cell surface components with co-stimulatory molecules of antigen presenting cells such as macrophages. in addition to CD3 signals, to resist CD95-mediated apoptosis. This difference in sensitivity to apoptosis of the two Th subsets is due to selective upregulation of phosphatidylinositol 3'-kinase (PI3""""""""-K) activity in Th2 clones following CD3 ligation. The upregulation of PI3'-K activity abrogates apoptosis by inhibiting CD95 aggregation in the membrane thereby blocking subsequent activation of the death effector molecule. caspase-S. Thus, activation of Thl cells, in a manner akin to antigen stimulation in the absence of co-stimulation, results in their apoptosis. Importantly, we have observed that expression of the B7 co-stimulatory molecule is down-regulated in M. tuberculosis-infected macrophages. Based on these observations. we propose to test the hypotheses that i,) in tuberculous infection, CD95-mediated Thi depletion occurs, resulting in attenuation of protective immunity against M. tuberculosis, thereby enhancing disease susceptibility; ii) downregulation of the expression of the B 7 class of costimulalory molecules contributes to Thi apoptosis. It is hoped that elucidation of the mechanisms underlying CD95-mediated Thi death in tuberculosis will help develop strategies to enhance protective immunity against the tubercle bacillus via specific disengagement of the apoptosis machinery in ThI cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI049778-02S1
Application #
6584377
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Sizemore, Christine F
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$65,171
Indirect Cost
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Bhatt, Kamlesh; Uzelac, Aleksandra; Mathur, Sanjeev et al. (2009) B7 costimulation is critical for host control of chronic Mycobacterium tuberculosis infection. J Immunol 182:3793-800
Bhatt, Kamlesh; Salgame, Padmini (2007) Host innate immune response to Mycobacterium tuberculosis. J Clin Immunol 27:347-62
Salgame, Padmini (2005) Host innate and Th1 responses and the bacterial factors that control Mycobacterium tuberculosis infection. Curr Opin Immunol 17:374-80