IL-23 and IL-1β Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation

Th17 cells drive autoimmune disease but also control commensal microbes. A common link among antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor (TCR) and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation...

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Veröffentlicht in:Cell reports (Cambridge) 2018-03, Vol.22 (10), p.2642-2653
Hauptverfasser: Revu, Shankar, Wu, Jing, Henkel, Matthew, Rittenhouse, Natalie, Menk, Ashley, Delgoffe, Greg M., Poholek, Amanda C., McGeachy, Mandy J.
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Sprache:eng
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Zusammenfassung:Th17 cells drive autoimmune disease but also control commensal microbes. A common link among antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor (TCR) and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation from human naive T cells, but not effector/memory cells. CD28 suppressed the classical Th17 transcriptional program, while inducing known Th17 regulators, and acted through an Akt-dependent mechanism. Th17 cells differentiated without CD28 were not anergic: they showed robust proliferation and maintained Th17 cytokine production following restimulation. Interleukin (IL)-23 and IL-1β promoted glucose uptake and increased glycolysis. Although modestly increased compared to CD28 costimulation, glycolysis was necessary to support Th17 differentiation, indicating that cytokine-mediated metabolic shifts were sufficient to obviate the classical requirement for CD28 in Th17 differentiation. Together, these data propose that, in humans, strength of TCR/CD28/Akt activation serves as a rheostat tuning the magnitude of Th17 development driven by IL-23 and IL-1β. [Display omitted] •CD28 costimulation is a suppressive modulator of human Th17 differentiation•Human Th17 cells differentiated without CD28 costimulation are not anergic•Partial inhibition of Akt restores CD28-suppressed Th17 development•IL-23/IL-1β drive moderately increased glucose uptake and glycolysis without CD28 CD28 costimulation is considered the requisite “signal 2” for T cell activation, driving aerobic glycolysis and preventing anergy. Revu et al. find that, for human Th17 cells, IL-23 and IL-1β provide sufficient signals for metabolic increases and avoidance of anergy, whereas CD28 costimulation suppresses induction of the Th17 transcriptional program.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.02.044