Guarda Greta, SNF Assistant Professor

In innate immune cells, the expression of pattern recognition receptors (PRRs), such as Toll-like, RIG-I-like, or NOD-like receptors (TLRs, RLRs, or NLRs) is crucial for the early detection of infection. Engagement of these receptors is essential for the onset of the inflammatory response and for the efficient presentation of foreign antigens to T lymphocytes.

In our group, we are interested in the study of PRRs, particularly in T cells. In fact, the role of these receptors has been well characterized in innate immune cells. However, specific PRRs are highly expressed by T lymphocytes, an aspect of adaptive immune responses 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 (adaptive immune system pathways).

One focus of our research is the study of novel NLRs poorly characterized and highly expressed in T lymphocytes. By using Nlrc5-deficient mice, we recently showed that NLRC5 is not involved in innate sensing, but acts instead as a transcriptional regulator of major-histocompatibility complex (MHC) class I, particularly in lymphocytes (Figure 1).
 

 
Fig. 1. Histograms show the expression of MHC class I (H-2K) on Nlrc5-deficient (Nlrc5 ko) and control (Nlrc5 floxed) T cells as measured by flow cytometry.

In the future, we would like to better understand different molecular aspects of NLRC5 activity, as schematically represented in Figure 2.

Fig. 2. Different molecular aspects of NLRC5 activity we would like to better understand: 1) which factors are involved in the transcriptional regulatory activity of NLRC5? 2) Which additional genes are controlled by NLRC5? 3) Are specific factors recruiting NLRC5 to the promoter region of MHC class I genes?

Moreover, the downregulation of MHC molecules is an established mechanism exploited by transformed or infected cells to evade immunosurveillance. We thus propose to explore the role of NLRC5 in preventing these pathologies by taking advantage of novel conditional Nlrc5-deficient mice and assessing NLRC5 expression and activity in primary human specimens. Indeed, we already found low NLRC5 expression in a panel of human and mouse lymphoid tumor cell lines (Figure 3). 

 

Fig. 3. NLRC5 expression in different human lymphoid tumor cell lines was assessed by immunoblot analysis (HD: healthy donor controls).
 

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 us to reconsider some of the features distinguishing innate from adaptive immunity, and may provide us with new opportunities for therapeutic intervention.

Full list of publications

Selected publications

• Staehli F, Ludigs K, Heinz LX, Ferrero I, Braun M, Schroder K, Rebsamen M, Tardivel A, Mattmann C, MacDonald HR, Romero P, Guarda G¹, Tschopp J¹. NLRC5-deficiency selectively impairs MHC class I-dependent lymphocyte killing by cytotoxic T cells. J Immunol. 2012 Apr 15;188(8):3820-8. doi: 10.4049/jimmunol.1102671. Epub 2012 Mar 12. ¹Shared senior authorship. 
• Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, Diavatopoulos DA, Wijburg O, Whitney PG, Heath WR, Curtis III R, Tschopp J, Bedoui S, Strugnell RA. NLRC4 inflammasome activation in splenic dendritic cells regulates non-cognate anti-bacterial effector function by memory CD8 T cells. Nat Immunol. 2012 Jan 8;13(2):162-9. doi: 10.1038/ni.2195.
• Gross O, Thomas CJ, Guarda G¹, Tschopp J¹. The inflammasome: an integrated view. Immunol Rev. 2011 Sep;243(1):136-51. doi: 10.1111/j.1600-065X.2011.01046.x. ¹Shared senior authorship. 
• Guarda G¹, Braun M¹, Staehli F, Tardivel A, Förster I, Farlik M, Decker T, Du Pasquier RA, Romero P, Tschopp J. Type I IFN inhibits IL-1 production and inflammasome activation. Immunity. 2011 Feb 25;34(2):213-23. doi: 10.1016/j.immuni.2011.02.006. ¹These two authors contributed equally to this work. 
• Guarda G¹, Zenger M¹, Yazdi A, Schroder K, Ferrero I, Menu P, Tardivel A, Mattmann C, Tschopp J. Differential NLRP3 expression among hematopoietic cells. J Immunol. 2011 Feb 15;186(4):2529-34. doi: 10.4049/jimmunol.1002720. Epub 2011 Jan 21. ¹These two authors contributed equally to this work. 
• Guarda G, Dostert C, Staehli F, Cabalzar K, Castillo R, Tardivel A, Schneider P, Tschopp J. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature. 2009 Jul 9;460(7252):269-73. doi: 10.1038/nature08100. Epub 2009 Jun 3.
• Guarda G, Hons M, Soriano SF, Huang A, Polley R, Martín-Fontecha A, Stein JV, Germain RN, Lanzavecchia A, Sallusto F. L-selectin-negative CCR7- effector and memory CD8+ T cells enter reactive lymph nodes and kill dendritic cells. Nat Immunol. 2007 Jul;8(7):743-52. Epub 2007 May 27.