Research Summary

Important discoveries come from fundamental research and 'How does this work' questions. For the past 15 years, I have studied mechanisms that regulate T cell responses and therefore regulate immune function, using cutting-edge real-time imaging methods to ask these kinds of questions. As a graduate student, I developed expertise in the generation and use of monoclonal antibodies targeted to costimulatory and inhibitory molecules on T cells. One of these projects developed antibodies to CTLA-4, which not only identified an inhibitory pathway of T cell regulation but also could be used to trigger or block that pathway. I subsequently applied these antibodies toward upregulating T cell responses to antigens in vivo and then toward augmenting immune responses to tumors. That approach led to the development of human antibodies of the same type, a therapy now named ipilimumab, and progressing toward FDA approval for treatment of melanoma and other cancers. I am firmly convinced that there is considerably more to be done with respect to modulating signaling in tumor microenvironments.

My lab now focuses on figuring out how immune systems--collections of cells in complex tissues--work. Our work capitalizes on using fluorescent proteins to track information processing by the immune system using imaging and/or flow cytometry. This has frequently taken the form of tagging and modulating components of the T cell receptor complex to understand the dynamics of signaling, as well as tagging and modulating motor proteins and other cytoskeletal proteins to study how these dynamics are controlled. These approaches have profited from considerable investments in developing novel imaging approaches. In addition, my lab emphasizes the use of fluorescent imaging approaches to understand how information is exchanged in the dense cellular milieu of organs.

We have developed imaging approaches to allow us to track T lymphocytes in lymph nodes, pancreas, lungs, and tumors. These are revealing unexpected dynamics of the assembly of complexes of lymphocytes and are paving the way to the types of studies defined herein--where key lymphocytes and stromal components begin again to be targeted with antibodies to disrupt interactions that likely control the local response. One exceptionally useful approach that we've developed is the generation of spontaneous models of breast cancer in which the stromal cells that interact with tumors become fluorescent by virtue of the uptake of very stable fluorescent protein variants. This enables us to focus on specific phagocytes in the tumor microenvironments and begin to characterize them as primary players in transmitting signals to lymphocytes and regulating disease outcome.

We continue to seek ways to understand basic biology and then facile means to translate that understanding into mechanisms for improving selectivity in the immune response.

Research Funding

  • April 1, 2008 - March 31, 2023 - Understanding Asthma Endotypes, Co-Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: U19AI077439
  • June 15, 2015 - May 31, 2020 - Manipulating collectivity and Niches for Developing CD8 Immunity, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01AI114787
  • September 1, 2015 - August 31, 2018 - Living Tumor Biopsies to Interrogate Immune Function and Response to Therapy, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R21CA196468
  • September 15, 2002 - December 31, 2017 - Cytoskeletal Regulation of T cell Motility and Synaptic Signaling, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01AI052116

Education

University of Illinois at Champaign-Urbana, B.S.+B.S., 1985-1989, Biology and Chemistry
University of California at Berkeley, Ph.D., 1989-1995, Immunology
Walter and Eliza Hall Institute, Melbourne Aus., 1996-1997, Immunology
Stanford University, 1997-2001, Immunology

Honors & Awards

  • 1986
    University of Illinois: James Scholar
  • 1996-1997
    Postdoctoral Fellowship, Juvenile Diabetes Foundation International
  • 1997-2000
    NRSA Postdoctoral Fellowship, National Institutes of Health
  • 2004-2007
    Investigator Award, Cancer Research Institute

Selected Publications

  1. You R, Artichoker J, Fries A, Edwards AW, Combes AJ, Reeder GC, Samad B, Krummel MF. Active surveillance characterizes human intratumoral T cell exhaustion. J Clin Invest. 2021 Sep 15; 131(18).  View on PubMed
  2. Weiner J, Suwalski P, Holtgrewe M, Rakitko A, Thibeault C, Müller M, Patriki D, Quedenau C, Krüger U, Ilinsky V, Popov I, Balnis J, Jaitovich A, Helbig ET, Lippert LJ, Stubbemann P, Real LM, Macías J, Pineda JA, Fernandez-Fuertes M, Wang X, Karadeniz Z, Saccomanno J, Doehn JM, Hübner RH, Hinzmann B, Salvo M, Blueher A, Siemann S, Jurisic S, Beer JH, Rutishauser J, Wiggli B, Schmid H, Danninger K, Binder R, Corman VM, Mühlemann B, Arjun Arkal R, Fragiadakis GK, Mick E, Comet C, Calfee CS, Erle DJ, Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Langelier CR, Venkataramani U, García F, Zyla J, Drosten C, Alice B, Jones TC, Suttorp N, Witzenrath M, Hippenstiel S, Zemojtel T, Skurk C, Wolfgang P, Borodina T, Pa-Covid SG, Ripke S, Sander LE, Beule D, Landmesser U, Guettouche T, Kurth F, Heidecker B. Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01. EClinicalMedicine. 2021 Sep 02; 101099.  View on PubMed
  3. Mehta P, Gouirand V, Boda DP, Zhang J, Gearty SV, Zirak B, Lowe MM, Clancy S, Boothby I, Mahuron KM, Fries A, Krummel MF, Mankoo P, Chang HW, Liu J, Moreau JM, Scharschmidt TC, Daud A, Kim E, Neuhaus IM, Harris HW, Liao W, Rosenblum MD. Layilin Anchors Regulatory T Cells in Skin. J Immunol. 2021 10 01; 207(7):1763-1775.  View on PubMed
  4. Sarma A, Christenson SA, Byrne A, Mick E, Pisco AO, DeVoe C, Deiss T, Ghale R, Zha BS, Tsitsiklis A, Jauregui A, Moazed F, Detweiler AM, Spottiswoode N, Sinha P, Neff N, Tan M, Serpa PH, Willmore A, Ansel KM, Wilson JG, Leligdowicz A, Siegel ER, Sirota M, DeRisi JL, Matthay MA, COMET Consortium , Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Erle DJ, Calfee CS, Langelier CR. Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS. Nat Commun. 2021 08 26; 12(1):5152.  View on PubMed
  5. van der Wijst MGP, Vazquez SE, Hartoularos GC, Bastard P, Grant T, Bueno R, Lee DS, Greenland JR, Sun Y, Perez R, Ogorodnikov A, Ward A, Mann SA, Lynch KL, Yun C, Havlir DV, Chamie G, Marquez C, Greenhouse B, Lionakis MS, Norris PJ, Dumont LJ, Kelly K, Zhang P, Zhang Q, Gervais A, Le Voyer T, Whatley A, Si Y, Byrne A, Combes AJ, Rao AA, Song YS, Fragiadakis GK, Kangelaris K, Calfee CS, Erle DJ, Hendrickson C, Krummel MF, Woodruff PG, Langelier CR, Casanova JL, Derisi JL, Anderson MS, Ye CJ, UCSF COMET consortium . Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci Transl Med. 2021 09 22; 13(612):eabh2624.  View on PubMed
  6. Combes AJ, Courau T, Kuhn NF, Hu KH, Ray A, Chen WS, Chew NW, Cleary SJ, Kushnoor D, Reeder GC, Shen A, Tsui J, Hiam-Galvez KJ, Muñoz-Sandoval P, Zhu WS, Lee DS, Sun Y, You R, Magnen M, Rodriguez L, Im KW, Serwas NK, Leligdowicz A, Zamecnik CR, Loudermilk RP, Wilson MR, Ye CJ, Fragiadakis GK, Looney MR, Chan V, Ward A, Carrillo S, UCSF COMET Consortium , Matthay M, Erle DJ, Woodruff PG, Langelier C, Kangelaris K, Hendrickson CM, Calfee C, Rao AA, Krummel MF. Publisher Correction: Global absence and targeting of protective immune states in severe COVID-19. Nature. 2021 Aug; 596(7872):E8.  View on PubMed
  7. Pipathsouk A, Brunetti RM, Town JP, Graziano BR, Breuer A, Pellett PA, Marchuk K, Tran NT, Krummel MF, Stamou D, Weiner OD. The WAVE complex associates with sites of saddle membrane curvature. J Cell Biol. 2021 08 02; 220(8).  View on PubMed
  8. Hysenaj L, Little S, Kulhanek K, Gbenedio OM, Rodriguez L, Shen A, Lone JC, Lupin-Jimenez LC, Bonser LR, Serwas NK, Bahl K, Mick E, Li JZ, Ding VW, Matsumoto S, Maishan M, Simoneau C, Fragiadakis G, Jablons DM, Langelier CR, Matthay M, Ott M, Krummel M, Combes AJ, Sil A, Erle DJ, Kratz JR, Roose JP. SARS-CoV-2 infection studies in lung organoids identify TSPAN8 as novel mediator. bioRxiv. 2021 Jun 02.  View on PubMed
  9. Cueto FJ, Del Fresno C, Brandi P, Combes AJ, Hernández-García E, Sánchez-Paulete AR, Enamorado M, Bromley CP, Gomez MJ, Conde-Garrosa R, Mañes S, Zelenay S, Melero I, Iborra S, Krummel MF, Sancho D. DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells. J Immunother Cancer. 2021 05; 9(5).  View on PubMed
  10. Tsitsiklis A, Zha B, Byrne A, DeVoe C, Levan S, Rackaityte E, Sunshine S, Mick E, Ghale R, Jauregui A, Neff N, Sarma A, Serpa P, Deiss T, Kistler A, Carrillo S, Ansel KM, Leligdowicz A, Christenson S, Jones N, Wu B, Darmanis S, Matthay M, Lynch S, DeRisi J, Consortium C, Hendrickson C, Kangelaris K, Krummel M, Woodruff P, Erle D, Rosenberg O, Calfee C, Langelier C. Impaired immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19. Res Sq. 2021 Apr 23.  View on PubMed
  11. Seed RI, Kobayashi K, Ito S, Takasaka N, Cormier A, Jespersen JM, Publicover J, Trilok S, Combes AJ, Chew NW, Chapman J, Krummel MF, Lou J, Marks J, Cheng Y, Baron JL, Nishimura SL. A tumor-specific mechanism of Treg enrichment mediated by the integrin αvβ8. Sci Immunol. 2021 Mar 26; 6(57).  View on PubMed
  12. Tsitsiklis A, Zha BS, Byrne A, Devoe C, Levan S, Rackaityte E, Sunshine S, Mick E, Ghale R, Jauregui A, Sarma A, Neff N, Serpa PH, Deiss TJ, Kistler A, Carrillo S, Ansel KM, Leligdowicz A, Christenson S, Jones N, Wu B, Darmanis S, Matthay MA, Lynch SV, DeRisi JL, COMET Consortium+ , Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Erle DJ, Rosenberg O, Calfee CS, Langelier CR. Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19. medRxiv. 2021 Mar 26.  View on PubMed
  13. Pinkard H, Baghdassarian H, Mujal A, Roberts E, Hu KH, Friedman DH, Malenica I, Shagam T, Fries A, Corbin K, Krummel MF, Waller L. Learned adaptive multiphoton illumination microscopy for large-scale immune response imaging. Nat Commun. 2021 03 26; 12(1):1916.  View on PubMed
  14. van der Wijst MGP, Vazquez SE, Hartoularos GC, Bastard P, Grant T, Bueno R, Lee DS, Greenland JR, Sun Y, Perez R, Ogorodnikov A, Ward A, Mann SA, Lynch KL, Yun C, Havlir DV, Chamie G, Marquez C, Greenhouse B, Lionakis MS, Norris PJ, Dumont LJ, Kelly K, Zhang P, Zhang Q, Gervais A, Voyer TL, Whatley A, Si Y, Byrne A, Combes AJ, Rao AA, Song YS, UCSF COMET consortium , Fragiadakis GK, Kangelaris K, Calfee CS, Erle DJ, Hendrickson C, Krummel MF, Woodruff PG, Langelier CR, Casanova JL, Derisi JL, Anderson MS, Ye CJ. Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19. bioRxiv. 2021 Mar 10.  View on PubMed
  15. Chan V, Gherardini PF, Krummel MF, Fragiadakis GK. A "data sharing trust" model for rapid, collaborative science. Cell. 2021 02 04; 184(3):566-570.  View on PubMed
  16. Combes AJ, Courau T, Kuhn NF, Hu KH, Ray A, Chen WS, Chew NW, Cleary SJ, Kushnoor D, Reeder GC, Shen A, Tsui J, Hiam-Galvez KJ, Muñoz-Sandoval P, Zhu WS, Lee DS, Sun Y, You R, Magnen M, Rodriguez L, Im KW, Serwas NK, Leligdowicz A, Zamecnik CR, Loudermilk RP, Wilson MR, Ye CJ, Fragiadakis GK, Looney MR, Chan V, Ward A, Carrillo S, UCSF COMET Consortium , Matthay M, Erle DJ, Woodruff PG, Langelier C, Kangelaris K, Hendrickson CM, Calfee C, Rao AA, Krummel MF. Global absence and targeting of protective immune states in severe COVID-19. Nature. 2021 03; 591(7848):124-130.  View on PubMed
  17. Sarma A, Christenson S, Mick E, Deiss T, DeVoe C, Pisco A, Ghale R, Jauregui A, Byrne A, Moazed F, Spottiswoode N, Sinha P, Zha B, Neff N, Tan M, Serpa PH, Ansel KM, Wilson J, Leligdowicz A, Seigel E, Sirota M, DeRisi J, Matthay M, Consortium C, Hendrickson C, Kangelaris K, Krummel M, Woodruff P, Erle D, Calfee C, Langelier C. COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone. Res Sq. 2021 Jan 14.  View on PubMed
  18. Krummel M, Hu K, de Vries EGE, Goetz JG, Passaro D, Subramaniam S, Misteli T, Skala M, Bravo-Cordero JJ, Sutcliffe JL. Visualizing Cancer. Cancer Cell. 2020 12 14; 38(6):753-756.  View on PubMed
  19. Argüello RJ, Combes AJ, Char R, Gigan JP, Baaziz AI, Bousiquot E, Camosseto V, Samad B, Tsui J, Yan P, Boissonneau S, Figarella-Branger D, Gatti E, Tabouret E, Krummel MF, Pierre P. SCENITH: A Flow Cytometry-Based Method to Functionally Profile Energy Metabolism with Single-Cell Resolution. Cell Metab. 2020 12 01; 32(6):1063-1075.e7.  View on PubMed
  20. Combes AJ, Courau T, Kuhn NF, Hu KH, Ray A, Chen WS, Cleary SJ, Chew NW, Kushnoor D, Reeder GC, Shen A, Tsui J, Hiam-Galvez KJ, Muñoz-Sandoval P, Zhu WS, Lee DS, Sun Y, You R, Magnen M, Rodriguez L, Leligdowicz A, Zamecnik CR, Loudermilk RP, Wilson MR, Ye CJ, Fragiadakis GK, Looney MR, Chan V, Ward A, Carrillo S, Matthay M, Erle DJ, Woodruff PG, Langelier C, Kangelaris K, Hendrickson CM, Calfee C, Rao AA, Krummel MF. Global Absence and Targeting of Protective Immune States in Severe COVID-19. bioRxiv. 2020 Oct 29.  View on PubMed

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