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

Abstract

<p id="P2">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 re-stimulation. 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. </p><p id="P3">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. </p><p id="P4"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/94516efd-6144-4ea3-86e6-419f0062ccc0/PubMedCentral/image/nihms953605u1.jpg"/> </div> </p>