Cutting Edge: CD28-Mediated Transcriptional and Posttranscriptional Regulation of IL-2 Expression Are Controlled through Different Signaling Pathways

Abstract

Despite the clear functional importance of CD28 costimulation, the signaling pathways transduced through CD28 have remained controversial. PI3K was identified early as a candidate for CD28 signaling, but conflicting data during the past decade has left the role of PI3K unresolved. In this report, we have resolved this controversy. We show that mutation of the PI3K interaction site in the cytosolic tail of CD28 site disrupts the ability of CD28 to recruit protein kinase C-θ to the central supramolecular activation cluster (c-SMAC) region of the immunological synapse, promote NF-κB nuclear translocation, and enhance IL-2 gene transcription. In contrast, mutation of the PI3K interaction site had no effect on the ability of CD28 to enhance IL-2 mRNA stability. These results suggest that two distinct pathways mediate CD28-induced up-regulation of IL-2 expression, a PI3K-dependent pathway that may function through the immunological synapse to enhance IL-2 transcription and a PI3K-independent pathway that induces IL-2 mRNA stability.

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

“…Although we show that steady-state IFN-γ transcripts are reduced, Tregs may mediate this effect by limiting the stabilization of the cytokine message rather than by a direct effect on transcription. CD28 signaling may override such regulation (36) and be sufficient to stabilize IL-2 and TNF-α but insufficient to stabilize IFN-γ.…”

Controlling NF-κB activation in T cells by costimulatory receptors

“…These mutants failed to recruit PKCy to the c-SMAC and thus to promote NF-kB activation. 49 In contrast, mutation of the PI3K interaction site still allowed CD28-mediated stabilization of IL-2 mRNA, showing that both mechanisms are distinctively regulated.…”

Rôle de CTLA-4 dans la cosignalisation négative du système immunitaire

“…La PKC-θ est recrutée par CD28 par un mécanisme qui implique le motif PYAP au niveau de la « synapse » immune [15]. La stabilisation des ARNm codant pour les cytokines dépendrait aussi de ce motif intracytoplasmique PYAP [12]. L'ensemble des fonctions de CD28 est donc induit par une combinaison d'effets dépendants de PI3K et d'effets liés au recrutement de différentes protéine kinases/molécules adaptatrices.…”

“…Deux motifs riches en proline, PRRP et PYAP, recrutent les domaines SH3 des PTK (protéine tyrosine kinase) Tec et Itk (PRRP) et Lck et Grb2 (PYAP) ainsi que la filamine A (FLNA) [11]. L'activité PI3K régule des fonctions comme la progression dans le cycle cellulaire, l'inhibition de l'apoptose, le métabolisme cellulaire et la production de cytokines [12,13]. Cependant, le recrutement de Grb2 et des PTK participe à la régulation des petites protéines GTPases et de réarran-gements du cytosquelette [11].…”