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Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation.

Accepted version
Peer-reviewed

Type

Article

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Authors

Queiroz, Rayner ML 
Piper, Siân C 
Strickson, Sam 
Briend, Emmanuel 

Abstract

The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin-1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin.

Description

Keywords

CYTIP/cytohesin, IL7, LFA, SPPLAT, TCR, phosphoproteomics, Actin Cytoskeleton, Blood Donors, Cells, Cultured, Guanine Nucleotide Exchange Factors, Humans, Interleukin-7, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Phosphorylation, Proteome, Proteomics, Receptors, Antigen, T-Cell, Recombinant Proteins, Signal Transduction, T-Lymphocytes, Threonine, Transcription Factors

Journal Title

Biochem J

Conference Name

Journal ISSN

0264-6021
1470-8728

Volume Title

Publisher

Portland Press Ltd.
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/J021091/1)