Low protease activity in B cell follicles promotes retention of intact antigens after immunization

Author:

Aung Aereas1ORCID,Cui Ang23ORCID,Maiorino Laura1ORCID,Amini Ava P.1345ORCID,Gregory Justin R.1,Bukenya Maurice1ORCID,Zhang Yiming16ORCID,Lee Heya1,Cottrell Christopher A.78ORCID,Morgan Duncan M.19ORCID,Silva Murillo1ORCID,Suh Heikyung1,Kirkpatrick Jesse D.13ORCID,Amlashi Parastoo1ORCID,Remba Tanaka1ORCID,Froehle Leah M.10ORCID,Xiao Shuhao1ORCID,Abraham Wuhbet1,Adams Josetta1ORCID,Love J. Christopher12910ORCID,Huyett Phillip11ORCID,Kwon Douglas S.10ORCID,Hacohen Nir212ORCID,Schief William R.8101314ORCID,Bhatia Sangeeta N.1231516ORCID,Irvine Darrell J.1681017ORCID

Affiliation:

1. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.

2. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

3. Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA.

4. Program in Biophysics, Harvard University, Boston, MA, USA.

5. Microsoft Research New England, Cambridge, MA, USA.

6. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

7. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.

8. Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA.

9. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

10. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.

11. Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA, USA.

12. Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

13. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.

14. IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.

15. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.

16. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

17. Howard Hughes Medical Institute, Cambridge, MA, USA.

Abstract

The structural integrity of vaccine antigens is critical to the generation of protective antibody responses, but the impact of protease activity on vaccination in vivo is poorly understood. We characterized protease activity in lymph nodes and found that antigens were rapidly degraded in the subcapsular sinus, paracortex, and interfollicular regions, whereas low protease activity and antigen degradation rates were detected in the vicinity of follicular dendritic cells (FDCs). Correlated with these findings, immunization regimens designed to target antigen to FDCs led to germinal centers dominantly targeting intact antigen, whereas traditional immunizations led to much weaker responses that equally targeted the intact immunogen and antigen breakdown products. Thus, spatially compartmentalized antigen proteolysis affects humoral immunity and can be exploited.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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