<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">
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