T cell receptor–triggered nuclear actin network formation drives CD4 ⁺ T cell effector functions

Abstract

T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4+T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca2+levels and regulated via N-Wasp and NIK. Specific interference with TCR-induced formation of nuclear actin filaments impairs production of effector cytokines and prevents generation of antigen-specific antibodies but does not interfere with immune synapse formation and cell proliferation. Ca2+-regulated actin polymerization in the nucleus allows CD4+T cells the rapid conversion of TCR signals into effector functions required for T cell help.

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells

“…It remains to be investigated, if some of those genes are targeted by the AHR directly and if the AHR is thereby able to impact on cytoskeleton and ion homeostasis. In αβ T cells the directed actin-polymerization in the nucleus and cytoplasm is triggered and controlled by the intracellular calcium concentration [54,55]. Despite the difference in the structure between the αβTCR and γδTCR and the lack of CD3δ subunit in the murine γδTCR-complex, the triggered signaling cascades include linker of activated T cell (LAT)-phosphorylation and calcium mobilization in both cell types [56,57].…”

Actin’ between phase separated domains for heterochromatin repair

“…These studies suggest a model where nuclear F-actin is mostly stimulusdriven, is highly dynamic, and mediates chromatin responses to different stresses 46,86 . Functions of nuclear F-actin include transcription regulation 82,84,85,87,88 , mitotic exit 85 , centromere maintenance 89 , replication origin activation 90 , replication fork rescue 91 , virus mobilization [92][93][94] , and DSB repair 39,53,83,95,96 (reviewed in 46,86 ).…”

Role of nuclear actin filaments in DNA repair dynamics

“…In addition to direct regulation of transcription factors by nuclear actin, a very recent study demonstrated the induction of cytokine expression in response to nuclear F-actin in activated T cells 33 . This occurs after T-cell receptor engagement in CD4+ cells such as during immunological synapse formation, and requires calcium elevations, N-Wasp, and nuclear Arp2/3 33 . As such, this study provides evidence for the importance of signalregulated nuclear actin polymerization in immune function.…”