Biology subjects

Garg, A. K.

Publications and source records attributed to Garg, A. K..

4 recordsLinked to original sources

bioRxiv2025

Multiple broadly neutralizing antibody lineages can co-exist and mature in the same germinal centres

An efficacious HIV vaccine will need to generate broadly neutralizing antibodies (bnAbs) against distinct viral epitopes. To facilitate this, immunogens targeting precursor B cells of bnAbs have been developed. With this strategy, individual immunogens can even target multiple lineages, thereby beneficially limiting the number of immunogens needed for a multi-bnAb generating vaccine. However, it is unclear whether this diminishes responses compared to isolated targeting of lineages with distinct immunogens. Here, we address this using an in silico model of naive B cell activation and affinity maturation in germinal centres. By incorporating (i) precursor properties and (ii) epitope masking by antibodies obtained from germinal centre-derived plasma cells, the model recapitulated features of bnAb lineage evolution as seen in pre-clinical mouse models. Subsequent model analysis suggested that under physiologically relevant conditions, priming of multiple bnAb lineages with a single immunogen was additive, thus, supporting the development of vaccines that target multiple lineages.

immunology↗

bioRxiv2022

Amount of antigen, T follicular helper cells and quality of seeder cells shape the diversity of germinal center B cells

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies.

immunology↗

bioRxiv2020

Functional Organization for Color Appearance Mechanisms in Primary Visual Cortex

Studies of color perception have led to mechanistic models of how cone-opponent signals from retinal ganglion cells are integrated to generate color appearance. But it is unknown how this hypothesized integration occurs in the brain. Here we show that cone-opponent signals transmitted from retina to primary visual cortex (V1) are integrated through highly organized circuits within V1 to implement the color opponent interactions required for color appearance. Combining intrinsic signal optical imaging (ISI) and 2-photon calcium imaging (2PCI) at single cell resolution, we demonstrate cone-opponent functional domains (COFDs) that combine L/M cone-opponent and S/L+M cone-opponent signals following the rules predicted from psychophysical studies of color perception. These give rise to an orderly organization of hue preferences of the neurons within the COFDs and the generation of hue "pinwheels". Thus, spatially organized neural circuits mediate an orderly transition from cone-opponency to color appearance that begins in V1.

neuroscience↗

bioRxiv2018

Stochastic simulations show how passive immunization can influence the germinal centre reaction and optimize host humoral responses

Passive immunization with antigen-specific antibodies was shown recently to induce lasting improvements in endogenous antibody production, raising the prospect of using passive immunization as a tool to engineer host humoral responses. The mechanism with which administered antibodies alter endogenous antibody production remains unknown. B cells that produce antigen-specific antibodies evolve and get selected in germinal centres (GCs). This selection requires that B cells acquire antigen presented in GCs. We hypothesized that passive immunization biases this selection in favour of B cells with high affinities for antigen. Administered antibodies form immune complexes with antigen which only B cells with higher affinities than the administered antibodies for antigen can rupture and acquire antigen, thus increasing the selection stringency in GCs. With this mechanistic hypothesis, we constructed a stochastic simulation model of the GC reaction. The simulations recapitulated and synthesized several independent experimental observations, presenting strong evidence in support of our hypothesis. Further, the simulations revealed a quality-quantity trade-off constraining the GC response. As the selection stringency increased, surviving B cells had higher affinities for antigen but fewer B cells survived. Increasing antigen availability in the GC relaxed this constraint. The affinity of the administered antibodies and/or antigen availability could thus be tuned to maximize the GC output. Comprehensively spanning parameter space, we predict passive immunization protocols that exploit the quality-quantity trade-off and maximize the GC output. Our study thus presents a new conceptual understanding of the GC reaction and a computational framework for the rational optimization of passive immunization strategies.\n\nSignificance statementWhen natural antibody production is inadequate, passive immunization with external antibodies can alleviate disease. Remarkably, passive immunization induced lasting improvements in natural antibody production in recent studies, suggesting that it could be deployed to engineer natural antibody responses. However, how administered antibodies alter natural antibody production remains unknown. B cells that produce antibodies targeting specific antigen evolve in germinal centres (GCs). We hypothesized that administered antibodies form complexes with antigen, preferentially allowing B cells with higher affinities to acquire antigen and be selected, thus altering antibody production. With this mechanistic hypothesis, we performed stochastic simulations of the GC reaction, which recapitulated experiments, unravelled a quality-quantity trade-off constraining the GC response, and predicted passive immunization protocols that maximized the GC output.

immunology↗