Antigen perception in T cells by long-term Erk and NFAT signaling dynamics

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (52), p.e2308366120
• Main Authors: Wither, Matthew J, White, William L, Pendyala, Sriram, Leanza, Paul J, Fowler, Douglas M, Kueh, Hao Yuan
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens - metabolism; Biological Sciences; Combinatorial analysis; Dynamics; Gene regulation; Histocompatibility Antigens - metabolism; Immune system; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Major Histocompatibility Complex; Mice; NF-AT protein; Peptides - metabolism; Perception; Physical Sciences; Protein Binding; Receptors, Antigen, T-Cell; Signal transduction; T cell receptors; T-Lymphocytes
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2308366120

Immune system threat detection hinges on T cells' ability to perceive varying peptide-major histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs but diverge only over longer (9+ h) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception and establish a framework for understanding T cell responses under diverse contexts.