Affinity maturation in a human humoral response to influenza hemagglutinin.

Publication Type:

Journal Article

Source:

Proc Natl Acad Sci U S A (2019)

Abstract:

<p>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&#39; unmutated common ancestor, &quot;UCA&quot;), 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&#39;s initial exposure and the vaccination that preceded sampling. Our data indicate that a &quot;pluripotent&quot; 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.</p>

PDB: 
6Q0E, 6Q0H, 6Q0I, 6Q0L, 6Q0O, 6Q18, 6Q19, 6Q1A, 6Q1E, 6Q1G, 6Q1J, and 6Q1K
Detector: 
HF4M
Beamline: 
24-ID-C
24-ID-E