Paper: Complex Antigens Drive Permissive Clonal Selection in Germinal Centers

ematsen · March 11, 2016, 2:47pm

Interesting new paper with @tbkepler and Kelsoe as senior authors:

ncbi.nlm.nih.gov

Complex Antigens Drive Permissive Clonal Selection in Germinal Centers.

M Kuraoka, AG Schmidt, T Nojima, F Feng, A Watanabe, D Kitamura, SC Harrison, TB Kepler and G Kelsoe, Immunity, Mar 2016 15

Germinal center (GC) B cells evolve toward increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten-specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens-Bacillus anthracis protective antigen and influenza hemagglutinin-in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naive B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early "winners" were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection.

One of the main points is that for real antigens, GC selection is “permissive”, meaning that a range of affinities for GC B cells is observed:

Particularly interesting for people interested in the effect of molecular substitution on affinity, they reconstruct phylogenetic trees and label them with affinities. We’ve seen this before for HIV BNAbs, but it’s neat to see data for other antigens appearing.

This other recent paper:

ncbi.nlm.nih.gov

Visualizing antibody affinity maturation in germinal centers.

JM Tas, L Mesin, G Pasqual, S Targ, JT Jacobsen, YM Mano, CS Chen, JC Weill, CA Reynaud, EP Browne, M Meyer-Hermann and GD Victora, Science (New York, N.Y.), 2016 04 03

Antibodies somatically mutate to attain high affinity in germinal centers (GCs). There, competition between B cell clones and among somatic mutants of each clone drives an increase in average affinity across the population. The extent to which higher-affinity cells eliminating competitors restricts clonal diversity is unknown. By combining multiphoton microscopy and sequencing, we show that tens to hundreds of distinct B cell clones seed each GC and that GCs lose clonal diversity at widely disparate rates. Furthermore, efficient affinity maturation can occur in the absence of homogenizing selection, ensuring that many clones can mature in parallel within the same GC. Our findings have implications for development of vaccines in which antibodies with nonimmunodominant specificities must be elicited, as is the case for HIV-1 and influenza.

also showed “permissive selection” in that certain rather poorly binding clonal lineages were observed at high frequency. [Credit: Trevor Bedford pointed this out during our journal club.]

Definitely some good material here for those working in mathematical models of GCs!