T cell; NOD-like receptors (NLRs); RIG-I-like receptors (RLRs); antiviral response; tumor surveillance; antigen presentation
Ludigs Kristina, Jandus Camilla, Utzschneider Daniel T., Staehli Francesco, Bessoles Stéphanie, Dang Anh Thu, Rota Giorgia, Castro Wilson, Zehn Dietmar, Vivier Eric, Held Werner, Romero Pedro, Guarda Greta (2016), NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions, in Nature Communications
, 7, 10554-10554.
Chelbi Sonia, Guarda Greta (2016), NLRC5, a promising new entry in tumor immunology., in J Immunother Cancer
Rota G., Ludigs K., Siegert S., Tardivel A., Morgado L., Reith W., De Gassart A., Guarda G. (2016), T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels, in The Journal of Immunology
, 196(7), 2939-2946.
Ludigs Kristina, Seguín-Estévez Queralt, Lemeille Sylvain, Ferrero Isabel, Rota Giorgia, Chelbi Sonia, Mattmann Chantal, MacDonald H Robson, Reith Walter, Guarda Greta (2015), NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module., in PLoS genetics
, 11(3), 1005088-1005088.
Dostert Catherine, Ludigs Kristina, Guarda Greta (2013), Innate and adaptive effects of inflammasomes on T cell responses., in Current opinion in immunology
, 25(3), 359-65.
Michallet Marie-Cécile, Rota Giorgia, Maslowski Kendle, Guarda Greta (2013), Innate receptors for adaptive immunity., in Current opinion in microbiology
, 16(3), 296-302.
Neerincx Andreas, Castro Wilson, Guarda Greta, Kufer Thomas A (2013), NLRC5, at the Heart of Antigen Presentation., in Frontiers in immunology
, 4, 397-397.
Yan Yiqing, Jiang Wei, Spinetti Thibaud, Tardivel Aubry, Castillo Rosa, Bourquin Carole, Guarda Greta, Tian Zhigang, Tschopp Jurg, Zhou Rongbin (2013), Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation., in Immunity
, 38(6), 1154-63.
Jankovic Dragana, Ganesan Jayanthi, Bscheider Michael, Stickel Natalie, Weber Felix C, Guarda Greta, Follo Marie, Pfeifer Dietmar, Tardivel Aubry, Ludigs Kristina, Bouazzaoui Abdellatif, Kerl Katrin, Fischer Julius C, Haas Tobias, Schmitt-Gräff Annette, Manoharan Anand, Müller Leonard, Finke Jürgen, Martin Stefan F, Gorka Oliver, Peschel Christian, Ruland Jürgen, Idzko Marco, Duyster Justus, Holler Ernst, The Nlrp3 inflammasome regulates acute graft-versus-host disease., in The Journal of experimental medicine
Antigen presenting cells (APCs) express a number of innate immune receptors called pattern recognition receptors (PRRs), which detect structures associated with invading pathogens or host-derived danger signals. Engagement of these receptors is crucial for the onset of the inflammatory response and for the efficient presentation of foreign antigens to T lymphocytes. It is commonly believed that T cells depend on APCs not only for their cognate activation, but also for the integration of important innate stimuli allowing a tailored response to pathogens. However, specific PRRs are highly expressed by T lymphocytes, an aspect of T cell biology that has been overlooked thus far. It is possible that these PRRs may provide T lymphocytes with functions resembling that of innate immune cells. Alternatively, proteins belonging to the PRR families may exert novel functions in roles more traditionally associated with T cell biology (antigen-specific, adaptive immune system pathways). This proposal aims to evaluate the T cell-intrinsic role of four PRRs; retinoic acid-inducible gene I (RIG-I), NOD-like receptor family member, pyrin domain containing (NLRP) 1, NLR family member, CARD domain containing (NLRC) 3 and NLRC5. These PRRs were selected on the basis of their predominant expression and negligible functional characterization in T lymphocytes. While no consensus exists on the roles of NLRC3 and NLRC5, RIG-I and NLRP1b (one out of three existing murine NLRP1 isoforms) are activated by pathogen-derived molecular patterns. However, it is unclear whether they fulfill such a function in T cells, and available data tend to disprove this hypothesis. We recently found that NLRC5 is not involved in innate sensing, but acts instead as an essential transcriptional regulator of MHCI in resting lymphocytes. As the downregulation of major-histocompatibility complex (MHC) molecules is an established mechanism exploited by transformed or infected cells to evade immunosurveillance, we propose to further explore the role of this NLR in preventing these pathologies, by taking advantage of novel conditional Nlrc5-deficient mice and assessing NLRC5 expression and activity in primary human specimens. NLRC3 is highly homologous to NLRC5 and CIITA, suggesting that it may similarly act as a transcriptional regulator of MHCs. However, its expression is reduced upon treatment with inflammatory stimuli, indicating that it may exert a negative regulatory function, a hypothesis that we will test in the newly generated conditional Nlrc3-deficient mice and by molecular approaches. Intriguingly, NLRP1 is phylogenetically related to the inflammatory family member NLRP3, raising the hypothesis that it may form an innate sensing platform in T cells. Finally, RIG-I expression is particularly elevated in T cells and modulated by TCR triggering. We will therefore address the molecular mechanism and the functional relevance of this previously unrecognized crosstalk between T cell activation and antiviral receptors by using knockout mouse models and biochemical means.As anticipated by our data on NLRC5, we expect that a detailed analysis of PRR function in T cells will reveal unexpected adaptive aspects of PRR signaling, or highlight unappreciated innate features of T lymphocytes. Both scenarios would be equally innovative and relevant to our knowledge of vertebrate immunology. This may lead to a careful reconsideration of our understanding of innate and adaptive immunity, and may provide us with new opportunities for therapeutic intervention.