Bulletin of the American Physical Society
APS March Meeting 2022
Volume 67, Number 3
Monday–Friday, March 14–18, 2022; Chicago
Session N04: ImmuneFocus Recordings Available
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Sponsoring Units: DBIO DSOFT Chair: Herbert Levine, Northeastern Univ Room: McCormick Place W-176C |
Wednesday, March 16, 2022 11:30AM - 12:06PM |
N04.00001: Decoding the specificity of the T cell repertoire: From random energy models to coarse-grained structure-based prediction Invited Speaker: Jason George The adaptive immune system enlists millions of T cells, each with a unique T cell receptor (TCR), to recognize and eliminate foreign and tumor associated antigens presented on the cell surface. Despite substantial interest, high-throughput and reliable identification of relevant TCR-antigen pairs remains a highly desired research objective. Predicting TCR-antigen specificity pairs on the level of the human T cell repertoire would have far-reaching applications in immunology and cancer immunotherapy, including improved design of tumor-specific T cells, optimized donor transplant selection, and characterization of T cell-mediated autoimmunity. The immense complexity required to understand how large (~108) TCR repertoires interact with thousands of potential antigens, together with increasingly available data on known TCR-antigen pairs, provides an attractive modeling problem well-suited to quantitative-based theoretical and computational investigation. Motivated by a statistical random energy model of TCR-antigen interactions, we describe the development of a structure-based, supervised machine learning model to resolve relevant TCR-antigen pairs from large immune repertoires and putative antigen lists. We utilize high affinity TCR-antigen pairs with their solved crystal structures to train an optimized energy model. Our results suggest that TCR-antigen pairs can be reliably predicted when training and testing pairs are restricted to the same MHC allele. We demonstrate the power of this approach by simulating the immunogenicity of a post-thymic selection immune system consisting of 109 TCR-antigen pairs. Lastly, we discuss recent applications trained on HLA A*02:01-restricted systems and the resulting transferability of our model to distinct TCRs and antigens, arguing for the utility of incorporating known structural information into the learning procedure for TCR-antigen interaction. |
Wednesday, March 16, 2022 12:06PM - 12:18PM |
N04.00002: Probing T cell thymic maturation through repertoire sequencing Francesco Camaglia, Erez Greenstein, Benjamin M Chain, Nir Friedman, Aleksandra M Walczak, Thierry Mora In order to protect themselves against external threats, vertebrates have developed an adaptive mechanism of immune defence where a leading role is played by T lymphocytes -- cells able to identify to short protein fragments of viral origin through a unique receptor. After the stochastic generation of the receptor, T cells undergo a selection process known as thymic maturation which aims at releasing into the host periphery only those cells with functional and weakly self-reactive receptors. From high-throughput sequencing of different repertoires FACS-sorted in the thymus provided, we use inference techniques to learn interpretable models for the selected features informative about the maturation cascade. Our results suggest that thymic maturation is a stochastic process of single cell promotion enhanced by cell-cell interactions. |
Wednesday, March 16, 2022 12:18PM - 12:30PM |
N04.00003: Quantifying shapes and dynamics of migrating T cells in 3D Henry Cavanagh, Robert G Endres, Maté Biro, Daryan Kempe T cells of the adaptive immune system use sophisticated shape dynamics to migrate towards and neutralize infected and cancerous cells. However, there is still limited quantitative understanding of the migration process in 3D extracellular matrices and across timescales. Here, we leverage recent advances in lattice light sheet microscopy for providing 3D videos at high spatiotemporal resolution to quantitatively explore the shape dynamics of migrating T cell in an unsupervised manner. We first develop a new shape descriptor based on spherical harmonics, and find that, despite any obvious constraints, the shape space of T cells is low dimensional with dynamics organized in ~50s 'motifs'. Using multi-scale wavelet analysis we show that these form a continuum, albeit with some frequently repeated ('stereotyped') motifs. Finally, we connect both shape and the organization of shape dynamic motifs to lab-frame behaviors such as 'turning', and put these in the context of previously established larger-scale migration modes. Our findings may improve the precision of therapeutic development, enable the comparison of T cell migration across different conditions (e.g. tissues, drugs and cell mutants), and more broadly stimulate discussion between researchers in animal and cell behavior. |
Wednesday, March 16, 2022 12:30PM - 12:42PM |
N04.00004: Cytotoxic T Lymphocyte Activation Signals Modulate Cytoskeletal Dynamics and Mechanical Force Generation Aashli Pathni, Altug Ozcelikkale, Ivan Rey-Suarez, Lei Li, Scott Davis, Nate Rogers, Zhengguo Xiao, Arpita Upadhyaya Cytotoxic T lymphocytes (CTLs) play a key role in the adaptive immune response by killing infected cells. CTL activation requires antigen presenting cells (APCs) to present pathogenic peptides and provide co-stimulatory signals to receptors on the CTL surface. Activated CTLs secrete lytic granules (LGs), containing enzymes that trigger target cell death, at the CTL-target junction or the immune synapse (IS). LGs are transported along microtubules to the IS, where secretion occurs in zones of actin depletion. Actomyosin-mediated force exertion at the IS further promotes target death. Cytokines such as interleukin-12 (IL-12), produced by APCs, act as a third signal for activation and enhance CTL function. We hypothesized that IL-12 modulates cytoskeletal dynamics at the IS, thus potentiating CTL function. We used TIRF microscopy to study cytoskeletal dynamics in murine CTLs activated in the presence of peptide and co-stimulation (two signals), or additionally with IL-12 (three signals). We found that three signal-activated CTLs display altered actomyosin flows, microtubule growth and LG speeds at the IS. We further showed that three signal-activated CTLs exert higher forces. Our results indicate a potential physical mechanism by which cytokines can augment the immune response. |
Wednesday, March 16, 2022 12:42PM - 1:18PM |
N04.00005: Modeling the Proinflammatory Microenvironment and Immune Response Dynamics During Infection Invited Speaker: Elebeoba May Intracellular pathogens like Francisella tularensis (Ft), a gram-negative Class A biothreat agent can trigger the release of cytokines, chemokines, and effector molecules into the microenvironment surrounding the infected cell, contributing to the formation of a proinflammatory microenvironment (PME). Immune cells recruited into the PME can be primed and activated by cytokine exposure promoting a more robust interaction between infiltrating immune cells and infected cells or, in the case of phagocytic cells, priming the cell to more effectively eliminate subsequent Ft infection. Macrophages and NK cells are central to the innate immune response to Ft and primary producers of TNF-α and IFN-γ, respective. Focusing on these key PME cytokines, which are found to modulate the in vivo response to Ft, we developed in silico and in vitro models to investigate the role of PME in macrophage activation and outcome of infection. Our results suggest that TNF-α priming does not significantly change the dynamics of Ft infection response, whereas IFN-γ priming significantly enhances the inflammatory response by up-regulating the macrophage effector response, endogenous TNF-α production, and the anti-inflammatory cytokine, IL10. |
Wednesday, March 16, 2022 1:18PM - 1:30PM |
N04.00006: The lifecycle of a B cell Zachary A Montague, Armita Nourmohammad B cells are the central actors in the adaptive system and encode highly diverse and mutable pathogen-engaging receptors. They can counter a multitude of pathogens by directly neutralizing invaders or by storing memory to respond to reinfections efficiently. Upon infection, activated B cells seed germinal centers (GCs) where they hypermutate and are selected for enhanced affinity to pathogens. On longer timescales, memory B cells from previous GC reactions can seed new GCs during reinfection and mutate further; however, the extent of their role in response to reinfections is unclear. Because B cells evolve only in GCs, standard dynamical models with continuous accumulation of mutations fail to describe this interrupted evolution. We introduce a stochastic telegraph process to model the B-cell lifecycle by capturing the entry and exit of B cells from GCs and constraining the accumulation of mutations to the GC residents only. We use this model to reconstruct time-resolved evolutionary histories of B cells from a longitudinal dataset of immune repertoires from individuals with HIV and obtain posteriors of the rates across repertoires and patients. Our results elucidate the lifecycle of B cells and clarify the role of memory B cells in secondary responses on a repertoire-wide scale. |
Wednesday, March 16, 2022 1:30PM - 1:42PM |
N04.00007: How slow delivery antigen modulates immunodominance upon immunization for difficult pathogens Leerang Yang, Arup K Chakraborty Immunodominance hierarchy of B cell epitopes on highly mutable pathogens such as HIV and influenza poses a hurdle for developing universal vaccines. Upon conventional immunization for these pathogens, most antibodies target highly-mutable distracting epitopes rather than the conserved target epitopes of broadly-neutralizing antibodies. Recent studies showed that slow delivery of immunogen via several closely-spaced injections modulates this hierarchy and boosts neutralizing antibody response against the subdominant epitopes. We developed a computational model to study the competition of B cells targeting two different epitopes on the same antigen, with immunodominance hierarchy imposed by the differences in naive B cell precursor frequency and affinity. Our model reveals potential mechanisms for how slow delivery of antigen boosts B cell response against the subdominant epitope. It can allow the recruitment of low-affinity or rare precursors during the early phase of the germinal center response. Alternatively, it can lead to a strong epitope-masking effect that modulates competition in the germinal center later. We identify conditions required for these mechanisms to be dominant. Moreover, using our model we evaluate the effect of changing the number, interval, and dosing profile of the injections to maximize the neutralization while minimizing the number of injections required. We find that even a small number of injections may recapitulate the beneficial effects of slow delivery. |
Wednesday, March 16, 2022 1:42PM - 1:54PM |
N04.00008: Immune cells use active tugging forces to rank affinity and accelerate evolution Hongda Jiang, Shenshen Wang Generation of potent antibodies relies on positive selection of immune B cells expressing high affinity receptors. Effective selection during B cell affinity maturation (a rapid evolutionary process) requires efficient ranking of affinities. Yet, the mechanism by which affinity discrimination is achieved and how it affects B cell evolution remains unclear. Growing evidence shows that B cells use mechanical forces to actively extract antigens from the surface of antigen-presenting cells. Here we study the stochastic process of antigen extraction using theory and simulations. We find that application of mechanical force alters the energy landscape of molecular interactions and consequently extends the range of distinguishable affinities. Integrating molecular extraction with population dynamics, we demonstrate that B cells may expend mechanical energy to accelerate affinity maturation. |
Wednesday, March 16, 2022 1:54PM - 2:06PM |
N04.00009: Immune training by evolving antigens Shenshen Wang, Jiming Sheng Highly mutable viruses evolve to evade host immunity that exerts selective pressure and adapts to viral dynamics. I will present a framework for identifying key determinants of the mode and fate of viral-immune coevolution, by linking molecular recognition and eco-evolutionary dynamics. We find that conservation level and initial diversity of antigen jointly determine the timing and efficacy of narrow and broad antibody responses, which in turn control the transition between viral persistence, clearance, and rebound. In particular, clearance of structurally complex antigens relies on antibody evolution in a larger antigenic space than where selection directly acts; viral rebound manifests binding-mediated feedback between ecology and rapid evolution. Finally, immune compartmentalization can slow viral escape but also delay clearance. This work suggests that flexible molecular binding allows a plastic phenotype that exploits potentiating variations outside direct contact, opening new and shorter paths toward highly adaptable states. |
Wednesday, March 16, 2022 2:06PM - 2:18PM |
N04.00010: Search and Localization Dynamics of the CRISPR-Cas9 System Qiao Lu, Simone Pigolotti, Deepak Bhat, Darya Stepanenko The CRISPR/Cas9 system acts as the prokaryotic immune system and has important applications in gene editing. The protein Cas9 is one of its crucial components. The role of Cas9 is to search for specific target sequences on the DNA and cleave them. We introduce a model of facilitated diffusion for Cas9 and fit its parameters to single-molecule experiments. Our model confirms that Cas9 search for targets by sliding, but shows that its sliding length is rather short. We then investigate how Cas9 explores a long stretch of DNA containing randomly placed targets. We solve this problem by mapping it into the theory of Anderson localization in condensed matter physics. We expand our model with hopping mechanism to rationalize experimental evidence on the distribution of Cas9 molecules along the DNA. The mapping to Anderson localization can be applied to other proteins that perform facilitated diffusion, to shed light on their dynamics and distribution along the DNA. |
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