Affinity maturation in a human humoral response to influenza hemagglutinin
Abstract
Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possiblemore »
- Authors:
-
- Boston Children's Hospital and Harvard Medical School, Boston, MA (United States)
- Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Broad Institute of MIT and Harvard, Cambridge, MA (United States)
- Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
- Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Ragon Inst. of Massachusetts General Hospital, Massachusetts Inst. of Technology, and Harvard, Cambridge, MA (United States)
- Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1581820
- Grant/Contract Number:
- P01 AI089618; U19 AI117892
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 116; Journal Issue: 52; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; influenza virus; antibody; B cell; vaccine; X-ray crystallography
Citation Formats
McCarthy, Kevin R., Raymond, Donald D., Do, Khoi T., Schmidt, Aaron G., and Harrison, Stephen C. Affinity maturation in a human humoral response to influenza hemagglutinin. United States: N. p., 2019.
Web. doi:10.1073/pnas.1915620116.
McCarthy, Kevin R., Raymond, Donald D., Do, Khoi T., Schmidt, Aaron G., & Harrison, Stephen C. Affinity maturation in a human humoral response to influenza hemagglutinin. United States. https://doi.org/10.1073/pnas.1915620116
McCarthy, Kevin R., Raymond, Donald D., Do, Khoi T., Schmidt, Aaron G., and Harrison, Stephen C. 2019.
"Affinity maturation in a human humoral response to influenza hemagglutinin". United States. https://doi.org/10.1073/pnas.1915620116. https://www.osti.gov/servlets/purl/1581820.
@article{osti_1581820,
title = {Affinity maturation in a human humoral response to influenza hemagglutinin},
author = {McCarthy, Kevin R. and Raymond, Donald D. and Do, Khoi T. and Schmidt, Aaron G. and Harrison, Stephen C.},
abstractNote = {Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possible alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.},
doi = {10.1073/pnas.1915620116},
url = {https://www.osti.gov/biblio/1581820},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 52,
volume = 116,
place = {United States},
year = {Mon Dec 16 00:00:00 EST 2019},
month = {Mon Dec 16 00:00:00 EST 2019}
}
Web of Science
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