The human group 1 CD1 molecules CD1a, CD1b, and CD1c have been shown to present both endogenous and mycobacterial-derived lipid antigens to various subsets of T cells. Group 1 CD1- restricted immune responses have been implicated in anti-mycobacterial immunity;however, their role in infection is unknown due to the lack of a suitable animal model. We have generated transgenic mice (hCD1Tg) that express human group 1 CD1 molecules in a pattern similar to humans, and support the development of T cells that are restricted to group 1 CD1. Both infection with Mycobacterium tuberculosis (Mtb) and immunization with Mtb lipids elicit group 1 CD1-restricted Mtb- lipid antigen-specific T cell responses in hCD1Tg mice, and secondary immunization induces more rapid responses than primary immunization. In addition, group 1 CD1-restricted T cells generated from hCD1Tg mice can recognize mycobacterial antigens described in humans. Taken together, these data indicate that group 1 CD1-restricted T cells play a role in adaptive immunity and could serve as targets for Mtb vaccine development. This proposal seeks to study the in vivo function of group 1 CD1-restricted T cells during Mtb infection and to test the efficacy of a lipid-based vaccine for Mtb that targets group 1 CD1-restricted T cells using the hCD1Tg mouse model.
In Aim 1, we propose to identify immunodominant Mtb antigens presented by group 1 CD1 in Mtb-infected hCD1Tg mice and evaluate the protective efficacy of these antigens in a lipid vaccine upon Mtb challenge.
In Aim 2, we propose to generate retrogenic mice which express TCRs specific to distinct Mtb lipid antigens, and investigate the activation kinetics, effector function, and protective role of these T cells using an adoptive transfer approach. While group 1 CD1-restricted Mtb lipid antigen-specific T cells recognize foreign antigens directly, group 1 CD1-restricted autoreactive T cells may be activated during infection through recognition of endogenous antigen presented by TLR-matured antigen presenting cells and contribute to innate anti-mycobacterial responses, analogous to what has been described for group 2 CD1d-restricted NKT cells. In our third Aim, we will therefore investigate the developmental requirements and function of autoreactive group 1 CD1-restricted T cells during Mtb infection using a TCR transgenic model. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted T cells contribute to protective immunity against Mtb and whether they can be targeted for the development of lipid antigen-based Mtb vaccines.
Tuberculosis (TB) remains the leading cause of death due to bacterial infection. In spite of this, an effective vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of TB, is lacking. Studies in humans have shown that various lipid components of the mycobacterial cell wall can be recognized by group 1 CD1-restricted T cells, however, the contribution of these T cells to immunity against Mtb is poorly understood. This study proposes to utilize novel animal models both to characterize the immune responses mediated by group 1 CD1-restricted T cells during Mtb infection, and to test the ability of lipid vaccines to confer resistance to Mtb infection.
|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|
|Choi, Hak-Jong; Xu, Honglin; Geng, Yanbiao et al. (2008) Bacterial infection alters the kinetics and function of iNKT cell responses. J Leukoc Biol 84:1462-71|
|Colmone, Angela; Li, Sha; Wang, Chyung-Ru (2006) Activating transcription factor/cAMP response element binding protein family member regulated transcription of CD1A. J Immunol 177:7024-32|