IL-6 trans-Signaling-Dependent Rapid Development of Cytotoxic CD8+ T Cell Function

•Rapid but transient granzyme B induction/cytotoxicity by LSECs occurs in CD8 T cells•IL-6 trans-signaling independent of CD28 and IL-12 triggers rapid GzmB induction•Superior activation potential of LSEC-primed CD8+ T cells supports ongoing immunity•Hyper-IL-6 is synergistic with dendritic cell-mediated effector T cell induction

SummaryImmune control of infections with viruses or intracellular bacteria relies on cytotoxic CD8+ T cells that use granzyme B (GzmB) for elimination of infected cells. During inflammation, mature antigen-presenting dendritic cells instruct naive T cells within lymphoid organs to develop into effector T cells. Here, we report a mechanistically distinct and more rapid process of effector T cell development occurring within 18 hr. Such rapid acquisition of effector T cell function occurred through cross-presenting liver sinusoidal endothelial cells (LSECs) in the absence of innate immune stimulation and known costimulatory signaling. Rather, interleukin-6 (IL-6) trans-signaling was required and sufficient for rapid induction of GzmB expression in CD8+ T cells. Such LSEC-stimulated GzmB-expressing CD8+ T cells further responded to inflammatory cytokines, eliciting increased and protracted effector functions. Our findings identify a role for IL-6 trans-signaling in rapid generation of effector function in CD8+ T cells that may be beneficial for vaccination strategies.

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