The human CD1 locus encodes five nonpolymorphic MHC class I-like molecules. These proteins, designated CD1a, CD1b, CD1c, CD1d, and CD1e are divided into two groups based on sequence homology. Group 2 CD1, comprising human CD1d, is present in all mammalian species examined so far, where as group 1 CD1, comprising human CD1a, CD1b, CD1c, is absent in rodents. Several studies have clearly shown that group1 CD1 molecules can present lipid/glycolipid antigens derived from Mycobacteria to cytotoxic T cells, suggesting that group 1 CD1 may play an important role in immune resistance to mycobacterial infections. The high degree of conservation of CD1-restricted microbial antigens and the low degree of polymorphism of CD1, make CD1 molecules attractive targets for T- cell based vaccines against intracellular pathogens for a diverse population. However, the absence of a suitable animal model for group1 CD1 has limited the in vivo analysis of the contribution of CD1-restricted T cells to specific immunological challenges. To overcome this limitation, we have generated transgenic mice (hCD1Tg) that express human CD1a, CD1b, and CD1c in a pattern similar to that seen in human tissues. This proposal aims to use thehCD1 transgenic mouse as an animal model to study the role of group 1 CD1-restricted responses in the defense against intracellular microbial pathogens, e.g. Mycobacterium tuberculosis and Listeria monocytogenes. We will also assess the immunogenicity of known CD1-restricted mycobacterial lipid antigens in hCD1Tg mice. ? In addition to presenting microbial lipid antigens, group 1 CD1 molecules appear to directly activate many human CD1-restricted T cells in the absence of foreign antigens. It has been postulated that these group 1CD1-restricted autoreactive T cells may serve to elicit antigen-independent immunity at an early phase of microbial infection. We will generate transgenic mice which express an autoreactive TCR specific to group 1CD1 and introduce them onto the hCD1Tg background to study the requirements for the selection and maintenance of group 1 CD1-restricted T cells. The activation status and functional properties of these group 1 CD1-restricted auto reactive T cells will be examined following Mycobacteria infection to see if they are involved in the immune response. Collectively, these studies will lead to a better understanding of the in vivo function of group 1 CD1 in infectious disease and T cell development. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057460-05
Application #
7320282
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-12-01
Project End
2008-04-30
Budget Start
2007-12-01
Budget End
2008-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$57,392
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Bagchi, Sreya; Genardi, Samantha; Wang, Chyung-Ru (2018) Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter. Front Immunol 9:1616
Bagchi, Sreya; He, Ying; Zhang, Hong et al. (2017) CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice. J Clin Invest 127:2339-2352
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:
Siddiqui, Sarah; Visvabharathy, Lavanya; Wang, Chyung-Ru (2015) Role of Group 1 CD1-Restricted T Cells in Infectious Disease. Front Immunol 6:337
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
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
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
Li, Sha; Choi, Hak-Jong; Felio, Kyrie et al. (2011) Autoreactive CD1b-restricted T cells: a new innate-like T-cell population that contributes to immunity against infection. Blood 118:3870-8
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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