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A forward genetic approach to uncover novel molecules required for NK cell function and CD8+ T cell priming

English title A forward genetic approach to uncover novel molecules required for NK cell function and CD8+ T cell priming
Applicant Krebs Philippe
Number 121410
Funding scheme Fellowships for advanced researchers
Research institution Department of Genetics The Scripps Research Institute
Institution of higher education Institution abroad - IACH
Main discipline Immunology, Immunopathology
Start/End 01.10.2008 - 30.06.2011
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All Disciplines (4)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology
Biochemistry
Molecular Biology

Keywords (9)

cross-talk innate/adaptive immunity; mutagenesis; natural killer (NK) cells; CD8+ T cells; genetic mapping; dendritic cell (DC) cross-priming; Toll-like receptor signaling; inflammation; cancer

Lay Summary (English)

Lead
Lay summary
We have used two different strategies to assess how the innate (fast, unspecific) immune system communicates with the adaptive (slower, specific, capable of memory) immune system.
A. In a hypothesis driven-approach, we have characterized a new and very sensitive pathway by which natural killer (NK) cell-mediated killing (innate immunity) leads to an efficient priming of T and B cells (adaptive effectors). This study assigns NK cells an important function at the interface of innate and adaptive immunity, which may be applied for vaccine design.
B. We have also screened randomly mutagenized mice to discover genes that make a non-redundant contribution to the communication between innate and adaptive immune defenses. Several mutant lines could be identified; some involving well-characterized proteins and pathways, some revealing so far poorly described genes, with sometimes phenotypes that were initially unexpected. These mutants can be proposed as novel models to investigate human conditions ranging from mitochondrial disease, autoimmunity, inflammatory bowel disease to cancer.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Publications

Publication
Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection.
Krebs Philippe (2015), Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection., in Proc Natl Acad Sci U S A, 112(42), E5706-E5714.
ENU-induced phenovariance in mice: Inferences from 587 mutations
Arnold C.N., Barnes M.J., Berger M., Blasius A.L., Brandl K., Croker B., Crozat K., Du X., Eidenschenk C., Georgel P., Hoebe K., Huang H., Jiang Z., Krebs P., La Vine D., Li X., Lyon S., Moresco E.M.Y., Murray A.R., Popkin D.L., Rutschmann S., Siggs O.M., Smart N.G., Sun L., Tabeta K. (2012), ENU-induced phenovariance in mice: Inferences from 587 mutations, in BMC Research Notes, 5(577), 1-14.
Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice
Wingender G., Stepniak D., Krebs P., Lin L., McBride S., Wei B., Braun J., Mazmanian S.K., Kronenberg M. (2012), Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice, in Gastroenterology, 143(2), 418-428.
Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection
Blasius A.L., Krebs P., Sullivan B.M., Oldstone M.B., Popkin D.L. (2012), Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection, in PLoS Pathogens, 8(9), 1-9.
Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice
Krebs P., Crozat K., Popkin D., Oldstone M.B., Beutler B. (2011), Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice, in Blood, 117(24), 6582-6588.
Impact of β2 integrin deficiency on mouse natural killer cell development and function
Crozat K., Eidenschenk C., Jaeger B.N., Krebs P., Guia S., Beutler B., Vivier E., Ugolini S. (2011), Impact of β2 integrin deficiency on mouse natural killer cell development and function, in Blood, 117(10), 2874-2882.
Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet
Krebs P., Fan W., Chen Y.-H., Tobita K., Downes M.R., Wood M.R., Sun L., Li X., Xia Y., Ding N., Spaeth J.M., Moresco E.M.Y., Boyer T.G., Lo C.W.Y., Yen J., Evans R.M., Beutler B. (2011), Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet, in Proceedings of the National Academy of Sciences of the United States of America, 108(49), 19678-19682.
Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice
Krieg L., Milstein O., Krebs P., Xia Y., Beutler B., Du X. (2011), Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice, in Blood, 118(24), 6418-6425.
A mutation of Ikbkg causes immune deficiency without impairing degradation of IκBα
Siggs O.M., Berger M., Krebs P., Arnold C.N., Eidenschenk C., Huber C., Pirie E., Smart N.G., Khovananth K., Xia Y., McInerney G., Karlsson Hedestam G.B., Nemazee D., Beutler B. (2010), A mutation of Ikbkg causes immune deficiency without impairing degradation of IκBα, in Proceedings of the National Academy of Sciences of the United States of America, 107(7), 3046-3051.
An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence
Berger M., Krebs P., Crozat K., Li X., Croker B.A., Siggs O.M., Popkin D., Du X., Lawson B.R., Theofilopoulos A.N., Xia Y., Khovananth K., Moresco E.M.Y., Satoh T., Takeuchi O., Akira S., Beutler B. (2010), An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence, in Nature Immunology, 11(4), 335-343.
Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency
Wingender G., Krebs P., Beutler B., Kronenberg M. (2010), Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency, in Journal of Immunology, 185(5), 2721-2729.
Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice
Freigang S., Zadorozhny V., McKinney M.K., Krebs P., Herro R., Pawlak J., Kain L., Schrantz N., Masuda K., Liu Y., Savage P.B., Bendelac A., Cravatt B.F., Teyton L. (2010), Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice, in Journal of Clinical Investigation, 120(6), 1873-1884.
Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells
Eidenschenk C., Crozat K., Krebs P., Arens R., Popkin D., Arnold C.N., Blasius A.L., Benedict C.A., Moresco E.M.Y., Xia Y., Beutler B. (2010), Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells, in Proceedings of the National Academy of Sciences of the United States of America, 107(21), 9759-9764.
Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice
Barnes M.J., Aksoylar H., Krebs P., Bourdeau T., Arnold C.N., Xia Y., Khovananth K., Engel I., Sovath S., Lampe K., Laws E., Saunders A., Butcher G.W., Kronenberg M., Steinbrecher K., Hildeman D., Grimes H.L., Beutler B., Hoebe K. (2010), Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice, in Journal of Immunology, 184(7), 3743-3754.
Commitment to the regulatory t cell lineage requires CARMA1 in the thymus but not in the periphery
Barnes M.J., Krebs P., Harris N., Eidenschenk C., Gonzalez-Quintial R., Arnold C.N., Crozat K., Sovath S., Moresco E.M., Theofilopoulos A.N., Beutler B., Hoebe K. (2009), Commitment to the regulatory t cell lineage requires CARMA1 in the thymus but not in the periphery, in PLoS Biology, 7(3), 0513-0524.
Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function
Blasius A.L., Brandl K., Crozat K., Xia Y., Khovananth K., Krebs P., Smart N.G., Zampolli A., Ruggeri Z.M., Beutler B.A. (2009), Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function, in Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2706-2711.
NK cell-mediated killing of target cells triggers robust antigen-specific T cell-mediated and humoral responses
Krebs P., Barnes M.J., Lampe K., Whitley K., Bahjat K.S., Beutler B., Janssen E., Hoebe K. (2009), NK cell-mediated killing of target cells triggers robust antigen-specific T cell-mediated and humoral responses, in Blood, 113(26), 6593-6602.
The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease
Xiao N., Eidenschenk C., Krebs P., Brandl K., Blasius A.L., Xia Y., Khovananth K., Smart N.G., Beutler B. (2009), The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease, in Journal of Immunology, 183(12), 7975-7983.

Associated projects

Number Title Start Funding scheme
189185 Role of mRNA splicing for shaping the intestinal environment 01.09.2020 Project funding (Div. I-III)
138188 Molecular dissection of microbe-induced immunopathlogy 01.09.2012 Project funding (Div. I-III)
138188 Molecular dissection of microbe-induced immunopathlogy 01.09.2012 Project funding (Div. I-III)
163086 mRNA splicing and epithelial integrity 01.04.2016 Project funding (special)

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