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Abstract
The cytokine content in tissue microenvironments shapes the functional capacity of a T cell. This capacity depends on the integration of extracellular signaling through multiple receptors, including the T-cell receptor (TCR), co-receptors, and cytokine receptors. Transforming growth factor β (TGF-β) signals through its cognate receptor, TGFβR, to SMAD family member proteins and contributes to the generation of a transcriptional program that promotes regulatory T-cell differentiation. In addition to transcription, here we identified specific signaling networks that are regulated by TGFβR. Using an array of biochemical approaches, including immunoblotting, kinase assays, immunoprecipitation, and flow cytometry, we found that TGFβR signaling promotes the formation of a SMAD3/4-protein kinase A (PKA) complex that activates C-terminal Src kinase (CSK) and thereby down-regulates kinases involved in proximal TCR activation. Additionally, TGFβR signaling potentiated CSK phosphorylation of the P85 subunit in the P85-P110 phosphoinositide 3-kinase (PI3K) heterodimer, which reduced PI3K activity and down-regulated the activation of proteins that require phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) for their activation. Moreover, TGFβR-mediated disruption of the P85-P110 interaction enabled P85 binding to a lipid phosphatase, phosphatase and tensin homolog (PTEN), aiding in the maintenance of PTEN abundance and thereby promoting elevated PtdIns(4,5)P2 levels in response to TGFβR signaling. Taken together, these results highlight that TGF-β influences the trajectory of early T-cell activation by altering PI3K activity and PtdIns levels.
Highlights
The cytokine content in tissue microenvironments shapes the functional capacity of a T cell
We took an immunoblotting approach to monitor the phosphorylation of LCK and ZAP70, which is another T-cell receptor (TCR) proximal kinase downstream of LCK, in murine CD4ϩ T cells activated through TCR, CD28 with and without transforming growth factor (TGF)- (Fig. 1A)
To establish the threshold required for TGF- receptor signaling to modulate LCK and ZAP70 phosphorylation, murine T cells were activated through the TCR and CD28 receptors in the presence of varying doses of TGF- (Fig. 1D)
Summary
The cytokine content in tissue microenvironments shapes the functional capacity of a T cell. To establish the threshold required for TGF- receptor signaling to modulate LCK and ZAP70 phosphorylation, murine T cells were activated through the TCR and CD28 receptors in the presence of varying doses of TGF- (Fig. 1D). To identify specific proteins that were tyrosine phosphorylated in response to TGFR signaling, T cells were activated through the TCR and CD28 receptors in the presence or absence of TGF-.
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