Research Summary

Dr. Locksley is the Director of the Sandler Asthma Basic Research Center (SABRE) and a Howard Hughes Medical Institute Investigator. He is a Professor in the Departments of Medicine and Microbiology & Immunology. He received his undergraduate degree in biochemistry from Harvard and his M.D. from the University of Rochester. After completing his residency at UCSF, he trained in infectious diseases at the University of Washington. Prior to his position as director of the SABRE Center, Dr. Locksley served 18 years as the Chief of the Division of Infectious Diseases at UCSF Medical Center. Dr. Locksley is a fellow of the American Academy of Arts and Sciences and member of the National Academy of Sciences.

Dr. Locksley's laboratory addresses the immune cells and tissue responses that occur during allergic, or type 2, immunity. This includes the processes by which naïve helper T cells differentiate to become allergy-supporting Th2 cells, but also the interactions of these cells with eosinophils, basophils, mast cells and alternatively activated macrophages that mediate activities in peripheral tissues. The laboratory increasingly focuses on innate immunity, particularly since the discovery of Group 2 innate lymphoid cells, or ILC2s, which are prominently involved in allergy. Importantly, the discovery of ILC2s initiated efforts to uncover the ‘ground state’ of allergy by investigating homeostatic pathways involving these cells that might provide insights regarding their primary function in the immune system and in homeostasis.

Dr. Locksley’s laboratory pioneered the use of mice genetically engineered to report cytokines expressed during allergic immune responses. Using these methods, the laboratory participated in the discovery of innate lymphoid type 2 cells, or ILC2s, which represent a previously unknown cell now implicated in allergic immunity. The ability to study the activation and organization of innate ILC2s uncovered a role for cells associated with allergy and asthma, such as eosinophils, in processes involved with basal metabolism and tissue homeostasis. Activation of ILC2s in the small intestine was implicated in alteration of the mucosa to a secretory phenotype characterized by high numbers of goblet cells and tuft cells. The latter, a previously mysterious epithelial cell of unknown function, was shown to be the source of IL-25, a cytokine capable of activating ILC2s and other immune cells associated with allergy and asthma, thus opening up entirely new avenues for discovery.

Research Funding

  • August 15, 2012 - July 31, 2024 - Exploring the biology of persistent type 2 airway niches in asthma , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01HL107202
  • July 1, 1988 - April 30, 2023 - Parasite immunity orchestrated by type 2 immune cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI026918
  • April 1, 2008 - March 31, 2023 - Understanding Asthma Endotypes , Co-Investigator . Sponsor: NIH, Sponsor Award ID: U19AI077439
  • August 1, 2000 - August 31, 2022 - Biology of Infectious Diseases Training Program , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: T32AI007641
  • July 1, 2015 - April 30, 2019 - Epithelial chitinase and lung homeostasis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL128903
  • January 1, 1991 - May 31, 2018 - Initiation of allergic immunity by parasites , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI030663
  • July 1, 1988 - March 31, 2017 - Parasite Immunity Orchestrated by Th2 Cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37AI026918
  • July 15, 2008 - June 30, 2014 - Innate immune regulation of inflammation and adaptive immunity , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01AI078869
  • September 30, 1996 - August 31, 2006 - Interactions of Lymphocytes, Cytokines and Airway Cells , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: P50HL056385
  • September 15, 1989 - June 30, 1993 - PSYCHOLOGICAL WELL-BEING OF LABORATORY-PAIRED PRIMATES , Co-Investigator . Sponsor: NIH, Sponsor Award ID: R01RR005355
  • September 30, 1983 - August 31, 1986 - HUMAN PHAGOCYTE FUNCTION IN HEALTH AND DISEASE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI019768

Education

Harvard College, Cambridge, MA, B.A., 1970, Biochemistry
Univ. of Rochester, Rochester, NY, M.D., 1976, Medicine
Univ. of California, San Francisco, CA, 1976-80, Resident, Chief Resident
Univ. Wash. School of Medicine, Seattle, WA, 1980-83, Infectious Diseases

Honors & Awards

  • American Society for Clinical Investigation, 1991
  • Burroughs Wellcome Fund Scholar in Molecular Parasitology, 1992-97
  • Fellow, Infectious Diseases Society of American, 1992
  • Association of American Physicians, 1994
  • Bailey K Ashford Medal, American Society Tropical Medicine and Hygiene, 1994
  • Ellison Medical Foundation Senior Scholar in Global Infectious Diseases, 2001-05
  • Distinguished Service Award, American Association of Immunologists, 2003
  • Inspirational Teacher Award, UCSF class of 2006
  • Sandler Distinguished Professorship, 2003
  • American Academy of Arts & Sciences, 2005
  • R37 MERIT Award, NIAID/NIH, 2006
  • 2017
    Member, National Academy of Sciences

Selected Publications

  1. Shaikh N, Waterhölter A, Gnirck AC, Becker M, Adamiak V, Henneken L, Wunderlich M, Hartmann W, Linnemann L, Huber TB, Krebs CF, Panzer U, Locksley RM, Wilhelm C, Breloer M, Turner JE. Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites. J Exp Med. 2023 Dec 04; 220(12).  View on PubMed
  2. Zwick RK, Kasparek P, Palikuqi B, Viragova S, Weichselbaum L, McGinnis CS, McKinley KL, Rathnayake A, Vaka D, Nguyen V, Trentesaux C, Reyes E, Gupta AR, Gartner ZJ, Locksley RM, Gardner JM, Itzkovitz S, Boffelli D, Klein OD. Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. bioRxiv. 2023 Sep 22.  View on PubMed
  3. Fahy JV, Locksley RM. Immune treatment tackles chronic obstructive pulmonary disease. Nature. 2023 Sep; 621(7979):476-477.  View on PubMed
  4. Díaz RE, Ecker AK, Correy GJ, Asthana P, Young ID, Faust B, Thompson MC, Seiple IB, Van Dyken SJ, Locksley RM, Fraser JS. Structural characterization of ligand binding and pH-specific enzymatic activity of mouse Acidic Mammalian Chitinase. bioRxiv. 2023 Jun 28.  View on PubMed
  5. Sbierski-Kind J, Cautivo KM, Wagner JC, Dahlgren MW, Nilsson J, Krasilnikov M, Mroz NM, Lizama CO, Gan AL, Matatia PR, Taruselli MT, Chang AA, Caryotakis S, O'Leary CE, Kotas M, Mattis AN, Peng T, Locksley RM, Molofsky AB. Group 2 innate lymphoid cells constrain type 3/17 lymphocytes in shared stromal niches to restrict liver fibrosis. bioRxiv. 2023 Apr 28.  View on PubMed
  6. Molofsky AB, Locksley RM. The ins and outs of innate and adaptive type 2 immunity. Immunity. 2023 04 11; 56(4):704-722.  View on PubMed
  7. Kotas ME, O'Leary CE, Locksley RM. Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage. Annu Rev Pathol. 2023 01 24; 18:311-335.  View on PubMed
  8. Ricardo-Gonzalez RR, Kotas ME, O'Leary CE, Singh K, Damsky W, Liao C, Arouge E, Tenvooren I, Marquez DM, Schroeder AW, Cohen JN, Fassett MS, Lee J, Daniel SG, Bittinger K, Díaz RE, Fraser JS, Ali N, Ansel KM, Spitzer MH, Liang HE, Locksley RM. Innate type 2 immunity controls hair follicle commensalism by Demodex mites. Immunity. 2022 10 11; 55(10):1891-1908.e12.  View on PubMed
  9. Kotas ME, Moore CM, Gurrola JG, Pletcher SD, Goldberg AN, Alvarez R, Yamato S, Bratcher PE, Shaughnessy CA, Zeitlin PL, Zhang IH, Li Y, Montgomery MT, Lee K, Cope EK, Locksley RM, Seibold MA, Gordon ED. IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function. JCI Insight. 2022 07 08; 7(13).  View on PubMed
  10. O'Leary CE, Sbierski-Kind J, Kotas ME, Wagner JC, Liang HE, Schroeder AW, de Tenorio JC, von Moltke J, Ricardo-Gonzalez RR, Eckalbar WL, Molofsky AB, Schneider C, Locksley RM. Bile acid-sensitive tuft cells regulate biliary neutrophil influx. Sci Immunol. 2022 03 04; 7(69):eabj1080.  View on PubMed
  11. Ricardo-Gonzalez RR, Molofsky AB, Locksley RM. ILC2s - development, divergence, dispersal. Curr Opin Immunol. 2022 04; 75:102168.  View on PubMed
  12. Cautivo KM, Matatia PR, Lizama CO, Mroz NM, Dahlgren MW, Yu X, Sbierski-Kind J, Taruselli MT, Brooks JF, Wade-Vallance A, Caryotakis SE, Chang AA, Liang HE, Zikherman J, Locksley RM, Molofsky AB. Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation. Immunity. 2022 02 08; 55(2):254-271.e7.  View on PubMed
  13. Castellanos CA, Ren X, Gonzalez SL, Li HK, Schroeder AW, Liang HE, Laidlaw BJ, Hu D, Mak ACY, Eng C, Rodríguez-Santana JR, LeNoir M, Yan Q, Celedón JC, Burchard EG, Zamvil SS, Ishido S, Locksley RM, Cyster JG, Huang X, Shin JS. Lymph node-resident dendritic cells drive TH2 cell development involving MARCH1. Sci Immunol. 2021 Oct 15; 6(64):eabh0707.  View on PubMed
  14. Gschwend J, Sherman SPM, Ridder F, Feng X, Liang HE, Locksley RM, Becher B, Schneider C. Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth. J Exp Med. 2021 10 04; 218(10).  View on PubMed
  15. Kotas ME, Mroz NM, Koga S, Liang HE, Schroeder AW, Ricardo-Gonzalez RR, Schneider C, Locksley RM. CISH constrains the tuft-ILC2 circuit to set epithelial and immune tone. Mucosal Immunol. 2021 11; 14(6):1295-1305.  View on PubMed
  16. O'Leary CE, Feng X, Cortez VS, Locksley RM, Schneider C. Corrections. Curr Protoc. 2021 Jul; 1(7):e205.  View on PubMed
  17. Kotas ME, Dion J, Van Dyken S, Ricardo-Gonzalez RR, Danel CJ, Taillé C, Mouthon L, Locksley RM, Terrier B. A role for IL-33-activated ILC2s in eosinophilic vasculitis. JCI Insight. 2021 06 22; 6(12).  View on PubMed
  18. Kastenschmidt JM, Coulis G, Farahat PK, Pham P, Rios R, Cristal TT, Mannaa AH, Ayer RE, Yahia R, Deshpande AA, Hughes BS, Savage AK, Giesige CR, Harper SQ, Locksley RM, Mozaffar T, Villalta SA. A stromal progenitor and ILC2 niche promotes muscle eosinophilia and fibrosis-associated gene expression. Cell Rep. 2021 04 13; 35(2):108997.  View on PubMed
  19. O'Leary CE, Feng X, Cortez VS, Locksley RM, Schneider C. Interrogating the Small Intestine Tuft Cell-ILC2 Circuit Using In Vivo Manipulations. Curr Protoc. 2021 Mar; 1(3):e77.  View on PubMed
  20. Bielecki P, Riesenfeld SJ, Hütter JC, Torlai Triglia E, Kowalczyk MS, Ricardo-Gonzalez RR, Lian M, Amezcua Vesely MC, Kroehling L, Xu H, Slyper M, Muus C, Ludwig LS, Christian E, Tao L, Kedaigle AJ, Steach HR, York AG, Skadow MH, Yaghoubi P, Dionne D, Jarret A, McGee HM, Porter CBM, Licona-Limón P, Bailis W, Jackson R, Gagliani N, Gasteiger G, Locksley RM, Regev A, Flavell RA. Skin-resident innate lymphoid cells converge on a pathogenic effector state. Nature. 2021 04; 592(7852):128-132.  View on PubMed

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