Memory CD8+ T cells are essential adaptive effector cells of immune defenses because they are extremely efficient at sensing intracellular pathogens and tumors. The chief effector feature of CD8+ T cells is their ability to recognize and kill infected and ?abnormal? cells but they also produce multiple effector cytokines and chemokines that contribute to orchestrate protective immune responses. The cellular and molecular stepwise mechanisms by which memory CD8+ T cells in vaccinated hosts are reactivated and mediate protection is not well understood. Answering to this question has the potential to lead to novel strategies to harness or redirect the power of CD8+ T cells to the benefit of the host in many therapeutic contexts. Over the years, using mice immunized with the intracellular bacterium Listeria monocytogenes (Lm) as model, we have contributed to show that during recall infection, vaccine-induced memory CD8+ T cells quickly sense sets of inflammatory cytokines released from various antigen-presenting cells (APCs), which initiate a rapid effector program in the memory CD8+ T cells. This includes notably the secretion of the potent immunomodulatory cytokine IFN? which further signals and activates microbicidal functions inside phagocytes, a necessary process for efficient protection of vaccinated hosts. Yet, IFN? is secreted to similar extent whether cognate T cell antigens are present or not. Protection, however, is antigen-specific, suggesting that other factors distinct from memory CD8+ T cell-derived IFN? account for IFN?-mediated protection. This proposal investigates these factors and their regulation in the memory CD8+ T cells, which APCs provide cognate antigen to the memory CD8+ T cells during recall infection and the dynamic interactions of memory CD8+ T cells and killer phagocytes using cutting-edge intravital imaging approaches. Finally, we will also dissect the mechanisms of IFN?-dependent cell-autonomous defenses that are triggered inside activated phagocytes. We predict successful completion of the proposed work will have a broad impact in the field of T cell biology and vaccines, and potentially important therapeutic implications.

Public Health Relevance

relevant statement This project has the potential to improve T cell therapies. Specifically, the proposal focuses on populations of white blood cells (leukocytes) that are induced upon vaccination of individuals and can protect against microbial infections and tumors. These cells are cytotoxic (CD8+) lymphocytes, and become long-lived upon vaccination, therefore are called 'memory' lymphocytes. They can express multiple functions that are important to protect the host against infectious microbes and to kill tumor cells. We studied and discovered that these cells protect vaccinated host by very precisely orchestrating the protective response of other leukocytes. We propose in this proposal to further dissect how they achieve such efficient elimination of invading microbial pathogens in vivo with the goal of designing novel immune therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI103338-07A1
Application #
9614704
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Kelly, Halonna R
Project Start
2012-12-15
Project End
2023-07-31
Budget Start
2018-08-14
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Lauvau, Grégoire; Boutet, Marie; Williams, Tere M et al. (2016) Memory CD8(+) T Cells: Innate-Like Sensors and Orchestrators of Protection. Trends Immunol 37:375-385
Chandrabos, Ceena; M'Homa Soudja, Saïdi; Weinrick, Brian et al. (2015) The p60 and NamA autolysins from Listeria monocytogenes contribute to host colonization and induction of protective memory. Cell Microbiol 17:147-63
Lauvau, Grégoire; Soudja, Saïdi M'Homa (2015) Mechanisms of Memory T Cell Activation and Effective Immunity. Adv Exp Med Biol 850:73-80
Lauvau, Grégoire; Loke, P'ng; Hohl, Tobias M (2015) Monocyte-mediated defense against bacteria, fungi, and parasites. Semin Immunol 27:397-409
Lauvau, Grégoire (2015) PI3-kinase, the key for bugs to get in? J Exp Med 212:127
Lauvau, Grégoire; Chorro, Laurent; Spaulding, Emily et al. (2014) Inflammatory monocyte effector mechanisms. Cell Immunol 291:32-40
Soudja, Saïdi M'Homa; Chandrabos, Ceena; Yakob, Ernest et al. (2014) Memory-T-cell-derived interferon-? instructs potent innate cell activation for protective immunity. Immunity 40:974-88
Ruiz, Anne L; Soudja, Saidi M'Homa; Deceneux, Cyril et al. (2014) NK1.1+ CD8+ T cells escape TGF-? control and contribute to early microbial pathogen response. Nat Commun 5:5150
Soudja, Saïdi M'Homa; Ruiz, Anne L; Marie, Julien C et al. (2012) Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 37:549-62