Biology subjects

Alkutkar, T.

Publications and source records attributed to Alkutkar, T..

2 recordsLinked to original sources

bioRxiv2025

Replaying germinal center evolution on a quantified affinity landscape

Darwinian evolution of immunoglobulin genes within germinal centers (GCs) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the cellular mechanics of how competition between B cells produces increases in affinity are well established, the evolutionary dynamics of this process are less clear. We developed an experimental evolution model where we "replay" over one hundred monoclonal GC reactions, assigning affinities to each cell using deep mutational scanning. Our data reveal how GCs achieve predictable outcomes by means of noisy but persistent selection on an affinity landscape whose exploration is heavily constrained by somatic hypermutation biases. We infer a fitness landscape that quantitatively recapitulates the affinity maturation trajectory of our clone and find that apparent features of GC selection such as permissiveness to low-affinity lineages and rapid plateauing of affinity are likely artifacts of survivorship biases that distort our view of how B cell affinity progresses over time.

immunology↗

bioRxiv2020

Convergence of a common solution to broad ebolavirus neutralization by glycan cap directed human antibodies

Antibodies that target the glycan cap epitope on ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization is not well-understood. Here we present cryo-electron microscopy (cryo-EM) structures of several glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLD) to the glycan cap, which we name the MLD-anchor and cradle. Antibodies that bind to the MLD-cradle share common features, including the use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form beta-hairpin structures to mimic the MLD-anchor, disrupt MLD attachment, destabilize GP quaternary structure and block cleavage events required for receptor binding. Our results collectively provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies.

immunology↗