Editors' ChoiceTCR Signaling

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Science Signaling  15 Oct 2019:
Vol. 12, Issue 603, eaaz7799
DOI: 10.1126/scisignal.aaz7799

Quantitative proteomics maps previously unappreciated interactions stimulated by T cell activation.

T cell activation stimulates not only transcriptional reprogramming but also global proteome remodeling. Howden et al. found some unexpected differences in the abundances of endogenous proteins after activation of primary T cells as assessed by quantitative, high-resolution mass spectrometry. For example, previously reported increases in the amounts of hexokinase 1 (HK1), HK2, and the receptor tyrosine phosphatase CD45 after T cell activation were negligible when the data were normalized to account for cell size. In contrast, T cell activation greatly increased the amounts of the amino acid transporters SLC1A5 and SLC7A5, mitochondrial solute transporters, as well as the innate immune signaling molecules cGAS, STING, TBK1, and IRF3 in both CD4+ and CD8+ T cells. This approach also revealed decreases in the abundances of cell cycle regulators after T cell activation, which were sensitive to the mTORC1 inhibitor rapamycin. These data may explain why rapamycin reduces the proliferation of naïve, but not activated, T cells.

In addition to changes in total abundance, after T cell receptor (TCR) stimulation, protein interactions are highly dynamic. Using high-resolution mass spectrometry and T cells from gene-targeted mice, Voisinne et al. mapped the involvement of 277 endogenous proteins in 366 high-confidence interactions that occurred after TCR stimulation over time. Many TCR-stimulated interactions were highly transient, such as those with the kinase Nck1, the adaptor Vav1, and the phospholipase PLC-γ, which formed within 30 s of TCR activation and were disassembled by the next time point tested. Incorporating protein abundance information with the dynamic protein interactomes suggested that the transmembrane adaptors CD5, CD6, and LAX1 may have more substantial roles in inhibiting TCR signaling than was previously appreciated. Several unexpected interactions that were identified suggested that TCR signaling proteins may also have previously unidentified functions; the kinase Lck unexpectedly interacted with proteins involved in nuclear translocation, and the FYBI adaptor proteins were involved in RNA splicing and stability. Together, these reports demonstrate the utility of a dynamic, protein-level assessment of T cell activation for understanding T cell function (see commentary by Conley and Berg), which suggests that similar dynamic assessment of CAR-T cell activation is warranted. Furthermore, these rich resources identify unexpected changes induced by T cell activation, which may explain the behavior of T cells in response to specific pharmacological inhibitors and may help guide the development of novel therapeutics for autoimmunity or rational cancer immunotherapy combinations.

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