CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity
Elise Gressier, Jonas Schulte-Schrepping, L. A. Petrov, Sophia Brumhard, Paula Stubbemann, Anna Hiller, Benedikt Obermayer, Jasper Spitzer, Tomislav Kostevc, Paul G. Whitney, Annabell Bachem, Alexandru Odainic, Carolien E. van de Sandt, Thi H. O. Nguyen, Thomas M. Ashhurst, Kayla R. Wilson, Clare V. Oates, Linden J. Gearing, Tina Meischel, Katharina Hochheiser, Marie Greyer, Michele V. Clarke, Maike Kreutzenbeck, Sarah S. Gabriel, Wolfgang Kastenmüller, Christian Kurts, Sarah L. Londrigan, Axel Kallies, Katherine Kedzierska, Paul J. Hertzog, Eicke Latz, Yu-Chen Enya Chen, Kristen J. Radford, Michaël Chopin, Jan Schröder, Florian Kurth, Thomas Gebhardt, Leif Erik Sander, Birgit Sawitzki, Joachim L. Schultze, Susanne V. Schmidt, Sammy Bedoui
Abstract
Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/β or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses. Bedoui and colleagues describe a sequential process of integration of innate and CD40-delivered signals in APCs, which optimizes their capacity to drive antiviral CD8+ T cell responses.