It is shown that TCR and IL2 signaling overlap in space and time and synergize when simultaneously triggered, demonstrating synergistic TCR and IL2R signaling that drives efficient expansion of antigen-specific CD8 + T cells.
Abstract
Interleukin 2 (IL2) promotes T cell proliferation and differentiation, making it a central target in immunotherapies. Following antigen recognition, IL2 receptor (IL2R) signaling polarizes towards the immunological synapse (IS). However, how IL2 function is integrated during earlier antigen-dependent T cell synapses remains unknown. Here, we employ a supported-lipid bilayer system and TIRF microscopy to monitor the IL2R subunits and their spatiotemporal organization relative to T cell receptor (TCR) at the IS of CD8
+
T cells. We show that TCR and IL2 signaling overlap in space and time and synergize when simultaneously triggered. Using Immuno-STATs, a class of immunotherapeutics in clinical testing that co-deliver IL2 and peptide major histocompatibility complex (pMHC), we demonstrate synergistic TCR and IL2R signaling that drives efficient expansion of antigen-specific CD8
+
T cells. Together, these findings establish the IS as a platform for coordinated cytokine and antigen receptor signaling, providing a mechanistic framework for more selective antigen-specific immunotherapies.
CD4+ cytotoxic T lymphocytes (CD4-CTLs) are understudied immune mediators with ambiguous origins. Despite expressing RUNX3, granzyme B (GZMB), and perforin (PRF1), CD4-CTLs are frequently classified as Th1 extensions due to shared interferon-γ (IFNγ) and T-BET expression. Here, we identify interleukin-27 (IL-27) as a i...
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Interleukin-12 (IL-12) is a key immunoregulatory cytokine produced primarily by antigen-presenting cells. During infection, IL-12 orchestrates innate immune responses and shapes the nature of subsequent adaptive immunity. Specifically, by promoting interferon-γ (IFN-γ) production in helper and cytolytic T cells and nat...
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Conventional methods for studying T-cell activation typically assess receptor engagement and downstream functional outputs in separate experimental formats, thereby obscuring the spatial correlation between initial receptor arrangement and localized functional outputs. This makes it difficult to examine the individual...
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Results indicate that IL-15Rα is spatially organised in proximity to both MHC class I and class II molecules on B-cell microvilli before immunological synapse formation, which may facilitate the coordination of IL-15 trans-presentation and antigen presentation during the earliest stages of B cell–T cell interactions.
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