Immune effector cell differentiation & protective host responses against microbial pathogens and tumors in vivo

We have three funded research themes in the laboratory that focus on:

1. The functional differentiation of naive and memory CD8⁺ T cells: we have built experimental systems in mice to assess the roles of cognate antigen in the functional fates of memory CD8 T cells and their ability to mediate host protection. Our goal is to provide a comprehensive understanding of i) how to generate functionally and epigenetically distinct memory CD8 T cells and ii) how to harness memory CD8 T cell protective mechanisms to the benefit of the host for new T cell therapies.

2. Immunity to malaria: we investigate i) the mechanisms of severe malaria, focusing on the role of type I interferon promoting poor clinical outcomes. We study a functional cell/cell interaction that occurs between macrophages and plasmacytoid dendritic cells in the bone marrow of infected mice and accounts for type I IFN production. We also investigate ii) the role of a subset of circulating memory CD4 T cells we found expanded in Malawian patients clinically protected against Plasmodium falciparum using cytometry by time of flight (CyTOF). We are conducting high throughput "omic" approaches to reveal and functionally test the CD4 T cell program associated with clinical protection against this number one killer parasite worldwide.

3. Anti-tumor immunity: we are using and characterizing a novel stem-cell based model of breast cancer in which several clinically relevant mutations have been introduced. This model mimics several key aspects of highly aggressive human breast cancers. We investigate mechanisms of immune escape and anti-tumor therapies. We are also exploring the immune response in the context of acute T cell lymphomas in HTLV1⁺ patients,

Our laboratory has developed multiple tools (pathogen, mice), as well as cutting edge approaches that include transcriptomic, single cell transcriptomics, epigenetic and intravital microscopy in close collaboration with other groups at Einstein. Our overall goal is to improve our fine understanding of the factors that orchestrate antimicrobial and antitumoral host protective immune responses in vivo. We believe that our work will contribute to more rationale design of immune cell-mediated preventative and therapeutic strategies.

Current laboratory members:

• Nicole Couturier, Ph. D. Student
• Erik Guillen, M.D./Ph. D. Student
• Jennifer Enright, Ph. D. Student
• Richard Garcia-Betancourt, Ph. D., Postdotoral Fellow

1. Furtado R.*, Paul M.*, Zhang J., Sung J., Karell P., Kim RS., Caillat-Zucman S., Liang L., Felgner P., Bauleni A., Gama S., Buchwald A., Taylor T., Seydel K., Laufer M, Delahaye F., Daily J.* and G. Lauvau*. Cytolytic memory CD4+ T cell clones are expanded during Plasmodium falciparum infection. Nature Communications 2023, 14: 7726.
2. Liu Y., John P., Nishitani K., Cui J. Nishimura C. D., Christin J., Couturier N., Ren X., Wei, Y., Pulanco M.C., Galbo P.M. Jr., Zhang X., Fu,W., Cui W.,  Bartholdy B. A., Zheng D., Lauvau G., Fineberg S., Oktay M.H., Zang X. and W. Guo. A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression. Developmental Cell 2023, in press.
3. Moore-Fried J., Paul M., Jing Z., Fooksman D.* and G. Lauvau*. CD169+ macrophages orchestrate plasmacytoid dendritic cell arrest and retention for optimal priming in the bone marrow of malaria-infected mice. eLife 2022, 11:e78873. 
4. Chin S.S.*, Guillen E.*, Chorro L., Achar S., Ng K., Oberle S., Alfei F., Zehn D., Altan-Bonnet G., Delahaye F.^* and G. Lauvau^*. T cell receptor and IL-2 signaling strength control memory CD8⁺ T cell functional fitness via chromatin remodeling. Nature Communications 2022, 13: 2240.
5. Boutet M., Benet Z., Delahaye F., Guillen E., Koch C., M’Homa Soudja S., Zehn D., Fooksman D. and G. Lauvau. Memory CD8+ T cells mediate early pathogen-specific protection via localized delivery of chemokines and IFNg to clusters of monocytes. Science Advances 2021, 7(36):eabf9975.
6. Furtado, R., Chorro L., Zimmerman N., Guillen E., Spaulding E., Chin S.S., Daily J.P. and G. Lauvau. Blockade of LAG-3 in PD-L1-deficient Mice Enhances Clearance of Blood Stage Malaria independently of humoral responses. Frontiers in Immunology 2021, 11:576743. PMC7840658
7. Clement CC, D'Alessandro A, Thangaswamy S, Chalmers S, Furtado R, Spada S, Mondanelli G, Ianni F, Gehrke S, Gargaro M, Manni G, Cara LCL, Runge P, Tsai WL, Karaman S, Arasa J, Fernandez-Rodriguez R, Beck A, Macchiarulo A, Gadina M, Halin C, Fallarino F, Skobe M, Veldhoen M, Moretti S, Formenti S, Demaria S, Soni RK, Galarini R, Sardella R, Lauvau G, Putterman C, Alitalo K, Grohmann U, Santambrogio L. 3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine. Nature Communications 2021, 12(1):4447. PMC8295276
8. Chin S.S., Chorro L., Chan J. and G. Lauvau. Splenic innate B1 B cell plasmablasts produce sustained GM-CSF and IL-3 cytokines during malaria infections. Inf and Immunity 2019, 87(12) e00482-19. PMC6867857
9. Zawieja D.C., Thangaswamy S., Wang W., Furtado R., Clement C.C., Papadopoulos Z., Vigano M., Bridenbaugh E.A., Zolla L., Gashev A.A., Kipnis J., Lauvau G. and L. Santambrogio. Lymphatic Cannulation for Lymph Sampling and Molecular Delivery, J Immunol 2019, 203:2339-2350.
10. Chorro L., Suzuki M., Williams T.M., Snapp E.L., Odagiu L., Labrecque N. and G. Lauvau. Interleukin 2 Modulates Functional Regulatory T Cell Epigenetic Landscape. Nature Communications 2018, 18;9(1):5368.
11. Li J, Chen M, Liu Z, Zhang L, Felding BH, Moremen KW, Lauvau G, Abadier M, Ley K, Wu P. A Single-Step Chemoenzymatic Reaction for the Construction of Antibody-Cell Conjugates. ACS Cent Sci 2018, 4:1633-1641. PMC6311947
12. Coelho C, Brown LC, Maryam M, Vij R, Smith DF, Burnet MC, Kyle JE, Heyman HM, Ramirez J, Prados-Rosales R, Lauvau G, Nakayasu ES, Brady NR, Hamacher-Brady A, Coppens I, Casadevall A. Listeria monocytogenes virulence factors, including Listeriolysin O, are secreted in biologically active Extracellular Vesicles. J Biol Chem 2018. PMC6349127
13. Spaulding E., D. Fooksman, A. Saidi, C. Feintuch, B. Reizis, J. Daily and G. Lauvau. STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria. PLoS Pathogens 2016, 12(10):e1005975.
14. Menezes S, Melandri D, Anselmi G, Perchet T, Loschko J, Dubrot J, Patel R, Gautier EL, Hugues S, Longhi MP, Henry JY, Quezada SA, Lauvau G, Lennon-Duménil AM, Gutiérrez-Martínez E, Bessis A, Gomez-Perdiguero E, Jacome-Galarza CE, Garner H, Geissmann F, Golub R, Nussenzweig MC, Guermonprez P. The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells. Immunity 2016, 45(6):1205-1218.
15. Subramaniam K.S., Spaulding E., Ivan E., Mutimura E., Kim R.S., Liu X., Dong C., Feintuch C.M., Zhang X., Anastos K., Lauvau G. and Daily J.P. The T cell inhibitory molecule BTNL2 is upregulated in mild Plasmodium falciparum infection and is protective during experimental cerebral malaria. J Infect Dis 2015, Apr 15. pii: jiv217..
16. Chandrabos C.*, M’Homa Soudja S. *, Weinrick B., Gros M., Frangaj A., Rahmoun M., Jacobs W.R. Jr. and G. Lauvau. The p60 and NamA Autolysins from Listeria monocytogenes Contributes to Host Colonization and Induction of Protective Memory. Cell Microbiol 2014, 17(2):147-63.
17. Anne L. Ruiz,, Saidi M’Homa Soudja, Cyril Deceneux, Grégoire Lauvau and Julien C. Marie. NK1.1+ CD8+ T Cells Escape TGFbeta control and Contribute to Early Microbial Pathogen response. 2014. Nature Communications 2014, 5:5150.
18. Soudja M’Homa S., Jacob E., Chandrabos C., M. Veenstra, Palliser D. and G. Lauvau. Memory T cell-derived IFN-g instructs potent innate cell activation for protective immunity. Immunity 2014, 40(6):974-88.
19. Arora P, Baena A, Yu KO, Saini NK, Kharkwal SS, Goldberg MF, Kunnath-Velayudhan S, Carreño LJ, Venkataswamy MM, Kim J, Lazar-Molnar E, Lauvau G, Chang YT, Liu Z, Bittman R, Al-Shamkhani A, Cox LR, Jervis PJ, Veerapen N, Besra GS, Porcelli SA. A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens. Immunity 2014. 40:105-16. PMC3895174
20. Soudja M’Homa S., Ruiz A. L., Marie J. C., and G. Lauvau. Inflammatory monocytes switch on memory CD8+ T and innate NK lymphocytes during microbial pathogens invasion. Immunity 2012, 37(3):549-62.
21. Narni-Mancinelli E., Soudja M’Homa S., Crozat K., Dalod M., Gounon P., Geissmann F. and G. Lauvau. Inflammatory monocytes and neutrophils are licensed to kill during Memory responses in vivo. PLoS Pathogens 2011, Vol 7(12):e1002457.
22. Campisi L., S. SoudjaM’Homa, N. Cagnard, J. Cazareth, D. Bassand, A. Lazzari, E. Narni-Mancinelli, F. Brau, N. Glaichenhaus, F. Geissmann and G. Lauvau. Splenic CD8a+ Dendritic Cells Undergo Rapid Programming by Cytosolic Bacteria and Inflammation to Induce Protective CD8 Memory. Eur J Immunol 2011, 41(6):1594-605.
23. Bajénoff M., Narni-Mancinelli E., Brau F., and G. Lauvau. Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria. PLoS One 2010, 5:11524.
24. Auffray C.*, D. K. Fogg*, E. Narni-Mancinelli*, B. Senechal, C. Touillet, N. Saederup, J. Leemput, K. Bigot, L. Campisi, M. Abitbol, T. Molina 1, I. Charo, D. A. Hume, A. Cumano, G. Lauvau and F. Geissmann. CX3CR1+ CD115+ CD135+ common macrophage/DC precursor (MDP) and the role of CX3CR1 in their response to inflammation. J Exp Med 2009, 206: 595-606.
25. Narni-Mancinelli E., L. Campisi, D. Bassand, J. Cazareth, P. Gounon, N. Glaichenhausand G. Lauvau. Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes. J Exp Med 2007, 204: 2075-2087.
26. Auffray, C., D. K. Fogg, Meriem Garfa, G. Elain, O. Join-Lambert, S. Kayal, S. Sarnacki, A. Cumano, G. Lauvau and F. Geissmann. Patrolling blood monocytes that monitor blood vessels and tissues for damage and infection. Science 2007, 317, 666-70.
27. Muraille, E.*, E. Narni-Mancinelli*, P. Gounon*, D. Bassand, N. Glaichenhaus, L. L. Lenz, and G. Lauvau. Cytosolic Expression of SecA2 is a Prerequisite for Long-Term Protective Immunity. Cell Microbiol 2007, 9, 1445-1454.
28. Muraille, E., R. Giannino, P. Guirnalda, I. Leiner, S. Jung, E. G. Pamerand G. Lauvau. 2005. Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes. Eur J Immunol 2005, 35:1-9.
29. Lauvau, G*., S. Culina*, B. Gubler, and P.M. van Endert. Calreticulin promotes folding of functional HLA class I molecules in vitro. J Biol Chem 2004, 279:54210-54215.
30. Lauvau, G.*, S. Vijh*, P. Kong, T. Horng, K. Kerksiek, N. Serbina, R.A. Tuma, and E.G. Pamer. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine.  Science 2001, 294:1735-1739.
31. Lauvau, G*., B. Gubler*, H. Cohen, S. Daniel, S. Caillat-Zucman, and P.M. van Endert. Tapasin enhances assembly of transporters associated with antigen processing-dependent and -independent peptides with HLA-A2 and HLA-B27 expressed in insect cells. J Biol Chem 1999, 274:31349-31358.
32. Lauvau, G., K. Kakimi, G. Niedermann, M. Ostankovitch, P. Yotnda, H. Firat, F.V. Chisari, and P.M. van Endert. 1999. Human transporters associated with antigen processing (TAPs) select epitope precursor peptides for processing in the endoplasmic reticulum and presentation to T cells. J Exp Med 1999, 190:1227-1240.

B. Review Articles/Chapters:

1. Lauvau, G and S. A. Porcelli. Chapter 20: Innate Immunity, Kelley & Firestein's Textbook of Rheumatology 11e, 2020.
2. Lauvau, G., M. Boutet, T.M. Williams, M. Shu Shien Chin and L. Chorro. Memory CD8+ T Cells: Innate-Like Sensors and Orchestrators of Protection. Trends in Immunology 2016, 37(6):375-85.
3. Lauvau, G. and S. Goriely. Memory CD8 T cells: Orchestrators and Key Players of Innate Immunity? PLoS Pathogens 2016, 12(9):e1005722.
4. Lauvau G., Loke P., Holh T.M. Monocyte Mediated Defense Against Pathogenic Microbes. Seminars in Immunology 2016, 27(6):397-409.
5. Lauvau G., S. M’Homa Soudja. Mechanisms of Memory T Cell Activation and Effective Immunity. Adv Exp Med Biol 2015, 850:73-80.
6. Lauvau G. 2015. PI3-kinase, the key for bugs to get in? J Exp Med, 9;212(2):127.
7. Lauvau G., L. Chorro, E. Spaulding, S. M’Homa Soudja. Inflammatory Monocyte Effector Mechanisms. Cellular Immunology 2014, S0008-8749(14)00125-7.
8. Lauvau G., M’Homa Soudja S., Chorro L. T cell Memory. Encyclopedia of Medical Immunology, I.R. Mackay, N.R. Rose (eds.), Springer Science 2013, DOI 10.1007/978-0-387-84828-0.
9. Geissmann F., C. Auffray, R. Palframan, C. Wirrig, A. Ciocca, L. Campisi, E. Narni-Mancinelli, and G. Lauvau. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T cell responses. Immunology and Cell Biology 2008, 86:398-408.