Both MHC class la and class Ib-restricted CD8+ T cells have been shown to participate in the immune response against intracellular bacteria infection. The kinetics and effector functions elicited by MHC class la- restricted T cells are well documented, however, less is known about antigen presentation by MHC class Ib molecules and the functions of their cognate T cells. H2-M3 is an MHC class Ib molecule which presents bacterial N-formylated peptides to T cells. Recent studies by our lab have shown that MS-restricted CD8+ T cells play a significant and nonredundant role in Listeria monocytogenes (LM) infection that bridges innate and adaptive immunity. Moreover, MS-restricted T cells can also be elicited during infection with Mycobacterium tuberculosis (Mtb). The significance of non-M3 class Ib-restricted T cells in bacterial infection remains to be defined. To investigate the unique early kinetics of MS-restricted T cells, we examined the development and function of these cells in TCR transgenic mice which express a TCR specific for M3/Listeria peptide complexes. We found that MS-restricted T cells can be positively selected by both hematopoietic cells and thymic epithelial cells, and that these two populations of MS-restricted T cells display different activation phenotypes. The objectives of this proposal are to determine how these distinct routes of selection contribute to the unique phenotype and function of MS-restricted T cells, and to determine the contribution of other non-M3 class Ib molecules to anti-microbial immunity. First, we will generate mixed bone marrow chimeras to elucidate which hematopoietic cells can select MS-restricted T cells. We will also compare the kinetics, effector functions, and memory phenotype of MS-restricted T cells selected by hematopoietic cells to those selected by thymic epithelial cells in the context of LM infection. Second, we will determine the kinetics and contribution of M3- and non-M3 class Ib-restricted T cell responses in LM and Mtb infection using class la-deficient and class la/MS-deficient mice. Finally, we will extend our study to identify other class Ib molecules which can present bacterial antigens through the generation of non-M3 class Ib-restricted T cell lines. Our studies on this relatively uncharacterized segment of the mammalian immunologic repertoire may lead to novel targets/methods for vaccination against infectious diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI040310-12
Application #
7473201
Study Section
Special Emphasis Panel (ZRG1-IMM-B (02))
Program Officer
Esch, Thomas R
Project Start
1996-07-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
12
Fiscal Year
2008
Total Cost
$333,295
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Bian, Yao; Shang, Shaobin; Siddiqui, Sarah et al. (2017) MHC Ib molecule Qa-1 presents Mycobacterium tuberculosis peptide antigens to CD8+ T cells and contributes to protection against infection. PLoS Pathog 13:e1006384
Zhao, Jie; Siddiqui, Sarah; Shang, Shaobin et al. (2015) Mycolic acid-specific T cells protect against Mycobacterium tuberculosis infection in a humanized transgenic mouse model. Elife 4:
Weng, Xiufang; Liao, Chia-Min; Bagchi, Sreya et al. (2014) The adaptor protein SAP regulates type II NKT-cell development, cytokine production, and cytotoxicity against lymphoma. Eur J Immunol 44:3646-57
Sena, Laura A; Li, Sha; Jairaman, Amit et al. (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225-36
Bediako, Yaw; Bian, Yao; Zhang, Hong et al. (2012) SAP is required for the development of innate phenotype in H2-M3--restricted Cd8(+) T cells. J Immunol 189:4787-96
Andrews, Daniel M; Sullivan, Lucy C; Baschuk, Nikola et al. (2012) Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells. Nat Immunol 13:1171-7
Cho, Hoonsik; Choi, Hak-Jong; Xu, Honglin et al. (2011) Nonconventional CD8+ T cell responses to Listeria infection in mice lacking MHC class Ia and H2-M3. J Immunol 186:489-98
Cho, Hoonsik; Bediako, Yaw; Xu, Honglin et al. (2011) Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8+ T cells. Proc Natl Acad Sci U S A 108:13241-6
Wang, T; Ahmed, E B; Chen, L et al. (2010) Infection with the intracellular bacterium, Listeria monocytogenes, overrides established tolerance in a mouse cardiac allograft model. Am J Transplant 10:1524-33
Felio, Kyrie; Nguyen, Hanh; Dascher, Christopher C et al. (2009) CD1-restricted adaptive immune responses to Mycobacteria in human group 1 CD1 transgenic mice. J Exp Med 206:2497-509

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