Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement
HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relie...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2020
|
| Online Access: | https://hdl.handle.net/1721.1/125968 |
| _version_ | 1826200895793135616 |
|---|---|
| author | Lofano, Giuseppe Gorman, Matthew J. Yousif, Ashraf S. Yu, Wen-Han Fox, Julie M. Dugast, Anne-Sophie Ackerman, Margaret E. Suscovich, Todd J. Weiner, Joshua Barouch, Dan Streeck, Hendrik Little, Susan Smith, Davey Richman, Douglas Lauffenburger, Douglas A Walker, Bruce Diamond, Michael S. Alter, Galit |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Lofano, Giuseppe Gorman, Matthew J. Yousif, Ashraf S. Yu, Wen-Han Fox, Julie M. Dugast, Anne-Sophie Ackerman, Margaret E. Suscovich, Todd J. Weiner, Joshua Barouch, Dan Streeck, Hendrik Little, Susan Smith, Davey Richman, Douglas Lauffenburger, Douglas A Walker, Bruce Diamond, Michael S. Alter, Galit |
| author_sort | Lofano, Giuseppe |
| collection | MIT |
| description | HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches. |
| first_indexed | 2024-09-23T11:43:26Z |
| format | Article |
| id | mit-1721.1/125968 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:43:26Z |
| publishDate | 2020 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1259682022-09-27T21:27:59Z Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement Lofano, Giuseppe Gorman, Matthew J. Yousif, Ashraf S. Yu, Wen-Han Fox, Julie M. Dugast, Anne-Sophie Ackerman, Margaret E. Suscovich, Todd J. Weiner, Joshua Barouch, Dan Streeck, Hendrik Little, Susan Smith, Davey Richman, Douglas Lauffenburger, Douglas A Walker, Bruce Diamond, Michael S. Alter, Galit Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Institute for Medical Engineering & Science HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches. National Institutes of Health (Grant R37AI080289) National Institutes of Health (Grant R01AI102660) 2020-06-23T21:48:39Z 2020-06-23T21:48:39Z 2018-08 2018-04 2020-03-12T15:57:42Z Article http://purl.org/eprint/type/JournalArticle 2470-9468 https://hdl.handle.net/1721.1/125968 Lofano, Giuseppe et al. "Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement." Science Immunology 3, 26 (August 2018): eaat7796 © 2018 The Authors en http://dx.doi.org/10.1126/sciimmunol.aat7796 Science Immunology Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf American Association for the Advancement of Science (AAAS) Science |
| spellingShingle | Lofano, Giuseppe Gorman, Matthew J. Yousif, Ashraf S. Yu, Wen-Han Fox, Julie M. Dugast, Anne-Sophie Ackerman, Margaret E. Suscovich, Todd J. Weiner, Joshua Barouch, Dan Streeck, Hendrik Little, Susan Smith, Davey Richman, Douglas Lauffenburger, Douglas A Walker, Bruce Diamond, Michael S. Alter, Galit Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement |
| title | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement |
| title_full | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement |
| title_fullStr | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement |
| title_full_unstemmed | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement |
| title_short | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement |
| title_sort | antigen specific antibody fc glycosylation enhances humoral immunity via the recruitment of complement |
| url | https://hdl.handle.net/1721.1/125968 |
| work_keys_str_mv | AT lofanogiuseppe antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT gormanmatthewj antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT yousifashrafs antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT yuwenhan antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT foxjuliem antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT dugastannesophie antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT ackermanmargarete antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT suscovichtoddj antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT weinerjoshua antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT barouchdan antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT streeckhendrik antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT littlesusan antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT smithdavey antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT richmandouglas antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT lauffenburgerdouglasa antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT walkerbruce antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT diamondmichaels antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement AT altergalit antigenspecificantibodyfcglycosylationenhanceshumoralimmunityviatherecruitmentofcomplement |