publications

2026

1. Design principles of the cytotoxic CD8+ T cell response

   Obinna A Ukogu, Zachary Montague, Grégoire Altan-Bonnet, and 1 more author

   Proc. Natl. Acad. Sci. U. S. A., Apr 2026

   Abs

   Cytotoxic T lymphocytes eliminate infected or malignant cells, safeguarding surrounding tissues. Although experimental and systems-immunology studies have cataloged many molecular and cellular actors involved in an immune response, the design principles governing how the speed and magnitude of T cell responses emerge from cellular decision-making remain elusive. Here, we recast the T cell response as a feedback-controlled program, wherein the rates of activation, proliferation, differentiation, and death are regulated through antigenic, pro- and anti-inflammatory cues. By exploring a broad class of feedback-controller designs as potential immune programs, we demonstrate how the speed and magnitude of T cell responses emerge from optimizing signal-feedback to protect against diverse infection settings. We recover an inherent trade-off: infection clearance at the cost of immunopathology. We show how this trade-off is encoded into the logic of T cell responses by hierarchical sensitivity to different immune signals. Notably, we find the designs that balance harm from acute infections and autoimmunity produce immune responses consistent with the experimentally observed patterns of T cell effector expansion in mice. Extending our model to immune-based T cell therapies for cancer tumors, we quantify the trade-off between the affinity for tumor antigens (“quality”) and the abundance (“quantity”) of infused T cells necessary for effective treatment. Finally, we show how therapeutic efficacy can be improved by targeted genetic perturbations to T cells. Our findings offer a unified control-logic for cytotoxic T cell responses and point to specific regulatory programs that can be engineered for more robust T cell therapies.

2024

1. Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision

   Kathleen Abadie, Elisa C Clark, Rajesh M Valanparambil, and 14 more authors

   Immunity, Feb 2024

   Abs

   The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.

2022

1. Waiting times in a branching process model of colorectal cancer initiation

   Ruibo Zhang, Obinna A Ukogu, and Ivana Bozic

   Theor. Popul. Biol., Jun 2022

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   We study a multi-stage model for the development of colorectal cancer from initially healthy tissue. The model incorporates a complex sequence of driver gene alterations, some of which result in immediate growth advantage, while others have initially neutral effects. We derive analytic estimates for the sizes of premalignant subpopulations, and use these results to compute the waiting times to premalignant and malignant genotypes. This work contributes to the quantitative understanding of colorectal tumor evolution and the lifetime risk of colorectal cancer.

2020

1. Protamine loops DNA in multiple steps

   Obinna A Ukogu, Adam D Smith, Luka M Devenica, and 8 more authors

   Nucleic Acids Res., Jun 2020

   Abs

   Protamine proteins dramatically condense DNA in sperm to almost crystalline packing levels. Here, we measure the first step in the in vitro pathway, the folding of DNA into a single loop. Current models for DNA loop formation are one-step, all-or-nothing models with a looped state and an unlooped state. However, when we use a Tethered Particle Motion (TPM) assay to measure the dynamic, real-time looping of DNA by protamine, we observe the presence of multiple folded states that are long-lived (∼100 s) and reversible. In addition, we measure folding on DNA molecules that are too short to form loops. This suggests that protamine is using a multi-step process to loop the DNA rather than a one-step process. To visualize the DNA structures, we used an Atomic Force Microscopy (AFM) assay. We see that some folded DNA molecules are loops with a ∼10-nm radius and some of the folded molecules are partial loops-c-shapes or s-shapes-that have a radius of curvature of ∼10 nm. Further analysis of these structures suggest that protamine is bending the DNA to achieve this curvature rather than increasing the flexibility of the DNA. We therefore conclude that protamine loops DNA in multiple steps, bending it into a loop.

2018

1. Quantum Jacobi forms and balanced unimodal sequences

   Michael Barnett, Amanda Folsom, Obinna Ukogu, and 2 more authors

   J. Number Theory, May 2018

   Abs

   The notion of a quantum Jacobi form was defined in 2016 by Bringmann and the second author in [1], marrying Zagier’s notion of a quantum modular form [12] with that of a Jacobi form. Only one example of such a function has been given to-date (see [1]). Here, we prove that two combinatorial rank generating functions for certain balanced unimodal sequences, studied previously by Kim, Lim and Lovejoy [8], are also natural examples of quantum Jacobi forms. These two combinatorial functions are also duals to partial theta functions studied by Ramanujan. Additionally, we prove that these two functions have the stronger property that they exhibit mock Jacobi transformations in C×H as well as quantum Jacobi transformations in Q×Q. As corollaries to these results, we use quantum Jacobi properties to establish new, simpler expressions for these functions as simple Laurent polynomials when evaluated at pairs of rational numbers.

2017

1. Optical methods for measuring DNA folding

   Adam D Smith, Obinna A Ukogu, Luka M Devenica, and 2 more authors

   Mod. Phys. Lett. B., Mar 2017

   Abs

   One of the most important biological processes is the dynamic folding and unfolding of deoxyribonucleic acid (DNA). The folding process is crucial for DNA to fit within the boundaries of the cell, while the unfolding process is essential for DNA replication and transcription. To accommodate both processes, the cell employs a highly active folding mechanism that has been the subject of intense study over the last few decades. Still, many open questions remain. What are the pathways for folding or unfolding? How does the folding equilibrium shift? And, what is the energy landscape for a particular process? Here, we review these emerging questions and the in vitro, optical methods that have provided answers, introducing the topic for those physicists seeking to step into biology. Specifically, we discuss two iconic experiments for DNA folding, the tethered particle motion (TPM) experiment and the optical tweezers experiment.