The Pieters Laboratory—Previous work

Here, our previous work leading up to the identification of the coronin signaling pathway regulating cell population size is described.

Characterization of the antigenic peptide-loading compartment in antigen presenting cells and identification of immune evasion mechanisms employed by M. tuberculosis

In early work, we unraveled the biochemical and cellular events of how antigens are processed and presented by antigen presenting cells by isolating and characterizing the long-sought intracellular compartment involved (1). Following up on this, the laboratory focused on investigating the mechanisms that allow the pathogen Mycobacterium tuberculosis to evade host immune destruction (2). We have analyzed both bacterial virulence factors as well as host factors that are being hijacked by M. tuberculosis. One important virulence factor that our laboratory has defined is protein kinase G (PknG), a eukaryotic-like serine/threonine protein kinase expressed by M. tuberculosis (3-5). This work was among the first demonstrations that pathogenic microbes have evolved to utilize eukaryotic-like signal transduction mechanisms for interfering with host immune cell activation pathways.

Discovery of host factors involved in the survival of M. tuberculosis

Besides releasing virulence factors within infected hosts, pathogenic microbes are known to hijack the host to avoid being killed, and our work has uncovered several of such strategies used by M. tuberculosis. First, we identified the plasma membrane component cholesterol as a host factor employed by M. tuberculosis to gain access to macrophages, cells that function as a survival niche for pathogenic mycobacteria (6). Second, we identified the host protein coronin 1 (aka tryptophan aspartate containing coat protein (TACO), or P57), a member of the highly conserved coronin protein family as a host factor involved in mycobacterial survival (7) and delineated the mechanism of coronin 1-mediated survival (2, 8-10). We further demonstrated that upon macrophage activation by inflammatory stimuli, coronin 1 is required for the induction of macropinocytosis through the activation of phosphatidylinositol (PI) 3 kinase activity (11). 

Uncovering a coronin 1-dependent signaling pathway essential for peripheral naïve T cell survival and cognition and behavior

Our work on coronin 1 and survival of M. tuberculosis within macrophages lead to the serendipitous finding that coronin 1 is essential for the survival of peripheral naïve T cells through its role in regulating signal transduction via cAMP/Ca2+-dependent pathways (8, 10, 12-14). Besides being expressed in immune cells, coronin 1 is expressed in a subset of neurons, and we subsequently found that coronin 1 regulates cognition and behavior through modulation of the cAMP/protein kinase A signaling pathway (13, 15).

Identification of a coronin 1-dependent signaling pathway specifically involved in auto- and allo immune responses and dispensable for immunity against pathogenic infections

In the course of our analysis of how coronin 1 regulates peripheral T cell numbers, we uncovered that disruption of coronin 1 signaling promotes tolerance towards autoimmune triggers and allografts, in the absence of immunosuppression-associated comorbidities (14). Mechanistically, we found that coronin 1-deficiency modulates cAMP levels to suppress allo-specific T cell responses without compromising pathogen-specific immunity (see also Ford, 2019: ‘Coronin 1-King of Alloimmunity’ Immunity 50:3-5). One of our future goals is to analyze the mechanisms underlying coronin 1-dependent regulatory axis in T cells important for auto and allo-immunity.

Coronin 1 and the establishment of the peripheral T cell population

Interestingly, while being essential for attaining and maintaining the appropriate number of T cells in the periphery, coronin 1 is dispensable for T cell development and selection (10, 12), which led us to suggest the existence of an unrecognized coronin 1-dependent decision switch early during life that is responsible for peripheral naive T cell survival and homeostasis (16). Subsequent work revealed the existence of a coronin 1–dependent PI3Kδ pathway that is independent of pMHC:TCR and IL-7 signaling and essential for peripheral T cell survival (17).

An evolutionarily conserved pathway controlling cell population size

Mammals express up to 7 coronin genes that may, in part, function in a redundant manner. Therefore, in parallel to our investigations in mammalian systems, we have employed the lower eukaryote Dictyostelium discoideum as a model system. These amoeba live as single cells that continuously sense their population density: When their cell density reaches a certain threshold amid limited food resources, instead of undergoing apoptosis, D. discoideum initiates a multicellular differentiation program to ensure their long-term survival. We found that in Dictyostelium, coronin is essential for cAMP-mediated initiation of starvation-induced multicellular differentiation (18).

 In ongoing and future work, we are aiming to unravel the mechanisms underlying coronin-dependent cell population size regulation using in vitro and in vivo experimental models, combined with cutting edge methodology such as whole cell transcriptomics, proteomics, single cell genomics, coupled high-end imaging and small molecule probe-based chemistry.

Key Publications

  1. Tulp, A., D. Verwoerd, B. Dobberstein, H.L. Ploegh, and J. Pieters. Isolation and characterization of the intracellular MHC class II compartment. Nature. 369:120-6 (1994). www.nature.com/articles/369120a0 | edoc

  2.  Pieters, J. Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe. 3:399-407 (2008). 10.1016/j.chom.2008.05.006. edoc | Open Access

  3.  Walburger, A., A. Koul, G. Ferrari, L. Nguyen, C. Prescianotto-Baschong, K. Huygen, B. Klebl, C. Thompson, G. Bacher, and J. Pieters. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science. 304:1800-4 (2004). 10.1126/science.1099384. edoc

  4. Scherr, N., S. Honnappa, G. Kunz, P. Mueller, R. Jayachandran, F. Winkler, J. Pieters, and M.O. Steinmetz. From the Cover: Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 104:12151-6 (2007). 10.1073/pnas.0702842104. edoc

  5. Houben, E.N., A. Walburger, G. Ferrari, L. Nguyen, C.J. Thompson, C. Miess, G. Vogel, B. Mueller, and J. Pieters. Differential expression of a virulence factor in pathogenic and non-pathogenic mycobacteria. Mol Microbiol. 72:41-52 (2009). 10.1111/j.1365-2958.2009.06612.x. edoc

  6. Gatfield, J. and J. Pieters. Essential role for cholesterol in entry of mycobacteria into macrophages. Science. 288:1647-50 (2000). 10.1126/science.288.5471.1647. edoc

  7. Ferrari, G., H. Langen, M. Naito, and J. Pieters. A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell. 97:435-47 (1999). 10.1016/S0092-8674(00)80754-0. edoc

  8. Jayachandran, R., V. Sundaramurthy, B. Combaluzier, P. Mueller, H. Korf, K. Huygen, T. Miyazaki, I. Albrecht, J. Massner, and J. Pieters. Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell. 130:37-50 (2007). 10.1016/j.cell.2007.04.043. edoc

  9. Gatfield, J., I. Albrecht, B. Zanolari, M.O. Steinmetz, and J. Pieters. Association of the Leukocyte Plasma Membrane with the Actin Cytoskeleton through Coiled Coil-mediated Trimeric Coronin 1 Molecules. Mol Biol Cell. 16:2786-98 (2005). 10.1091/mbc.E05-01-0042. edoc | Open Access

  10. Pieters, J., P. Muller, and R. Jayachandran. On guard: coronin proteins in innate and adaptive immunity. Nat Rev Immunol. 13:510-8 (2013). 10.1038/nri3465. edoc

  11. Bosedasgupta, S. and J. Pieters. Inflammatory stimuli reprogram macrophage phagocytosis to macropinocytosis for the rapid elimination of pathogens. PLoS Pathog. 10:e1003879 (2014). §  journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003879 | edoc

  12. Mueller, P., J. Massner, R. Jayachandran, B. Combaluzier, I. Albrecht, J. Gatfield, C. Blum, R. Ceredig, H.R. Rodewald, A.G. Rolink, and J. Pieters. Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering. Nat Immunol. 9:424-31 (2008). 10.1038/ni1570. edoc

  13. Jayachandran, R., X. Liu, S. Bosedasgupta, P. Muller, C.L. Zhang, D. Moshous, V. Studer, J. Schneider, C. Genoud, C. Fossoud, F. Gambino, M. Khelfaoui, C. Muller, D. Bartholdi, H. Rossez, M. Stiess, X. Houbaert, R. Jaussi, D. Frey, R.A. Kammerer, X. Deupi, J.P. de Villartay, A. Luthi, Y. Humeau, and J. Pieters. Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling. PLoS Biol. 12:e1001820 (2014). 10.1371/journal.pbio.1001820. edoc

  14. Jayachandran, R., A. Gumienny, B. Bolinger, S. Ruehl, M.J. Lang, G. Fucile, S. Mazumder, V. Tchang, A.K. Woischnig, M. Stiess, G. Kunz, B. Claudi, M. Schmaler, K. Siegmund, J. Li, S. Dertschnig, G. Hollander, E. Medina, U. Karrer, D. Moshous, D. Bumann, N. Khanna, S.W. Rossi, and J. Pieters. Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity. Immunity. 50:152-165 e8 (2019). 10.1016/j.immuni.2018.12.011. edoc | Open Access

  15. Liu, X., S. BoseDasgupta, R. Jayachandran, V. Studer, S. Ruhl, M. Stiess, and J. Pieters. Activation of the cAMP/protein kinase A signalling pathway by coronin 1 is regulated by cyclin-dependent kinase 5 activity. FEBS Lett. 590:279-87 (2016). 10.1002/1873-3468.12046. edoc

  16. Lang, M.J., M. Mori, J. Ruer-Laventie, and J. Pieters. A Coronin 1-Dependent Decision Switch in Juvenile Mice Determines the Population of the Peripheral Naive T Cell Compartment. J Immunol. 199:2421-2431 (2017). 10.4049/jimmunol.1700438. edoc

  17. Mori, M., J. Ruer-Laventie, W. Duchemin, P. Demougin, T. Ndinyanka Fabrice, M.P. Wymann, and J. Pieters. Suppression of caspase 8 activity by a coronin 1-PI3Kdelta pathway promotes T cell survival independently of TCR and IL-7 signaling. Science signaling. 14:eabj0057 (2021). 10.1126/scisignal.abj0057. edoc

  18. Vinet, A.F., T. Fiedler, V. Studer, R. Froquet, A. Dardel, P. Cosson, and J. Pieters. Initiation of multicellular differentiation in Dictyostelium discoideum is regulated by coronin A. Mol Biol Cell. 25:688-701 (2014). 10.1091/mbc.E13-04-0219. edoc | Open Access