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Identification of functional, short-lived isoform of linker for activation of T cells (LAT)

Genes & Immunity volume 15, pages 449–456 (2014)Cite this article

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Abstract

Linker for activation of T cells (LAT) is a transmembrane adaptor protein playing a key role in the development, activation and maintenance of peripheral homeostasis of T cells. In this study we identified a functional isoform of LAT. It originates from an intron 6 retention event generating an in-frame splice variant of LAT mRNA denoted as LATi6. Comparison of LATi6 expression in peripheral blood leukocytes of human and several other mammalian species revealed that it varied from being virtually absent in the mouse to being predominant in the cow. Analysis of LAT isoform frequency expressed from minigene splicing reporters carrying loss- or gain-of-function point mutations within intronic polyguanine sequences showed that these elements are critical for controlling the intron 6 removal. The protein product of LATi6 isoform (LATi6) ectopically expressed in LAT-deficient JCam 2.5 cell line localized correctly to subcellular compartments and supported T-cell receptor signaling but differed from the canonical LAT protein by displaying a shorter half-life and mediating an increased interleukin-2 secretion upon prolonged CD3/CD28 crosslinking. Altogether, our data suggest that the appearance of LATi6 isoform is an evolutionary innovation that may contribute to a more efficient proofreading control of effector T-cell response.

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Acknowledgements

This work has been supported by the Polish National Science Centre (NCN) project number 2012/05/B/NZ5/01339 and co-financed by the European Union as part of the European Social Fund. This research was in part supported by the Consejeria de Salud, Junta de Andalucia (Spain), Grant Number PI-0365-2013. We are grateful to Dr Jacek Bania, Aleksandra Orłowska and Marta Lisowska for discussions and expert technical assistance. We thank Dr Pawel Kisielow for critical reading of this manuscript

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Author notes

  1. M Kłossowicz and K Marek-Bukowiec: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Tumor Immunology, Laboratory of Tumor Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland

    M Kłossowicz, K Marek-Bukowiec, B Ścirka & A Miazek

  2. Department of Biomedicine, Department of Biomedicine, Biotechnology and Public Health (Immunology), Core Research Facility for Health Sciences, University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Biotechnology and Public Health (Immunology), Cadiz, Spain

    M M Arbulo-Echevarria & E Aguado

  3. Laboratory of Cytobiochemistry, Biotechnology Faculty, University of Wrocław, Wroclaw, Poland

    M Majkowski & A F Sikorski

  4. Department of Biochemistry, Pharmacology and Toxicology, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland

    A Miazek

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  1. M Kłossowicz
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Correspondence to A Miazek.

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All the authors performed experiments and analyzed results, AM and EA designed the study and AM wrote the manuscript.

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Kłossowicz, M., Marek-Bukowiec, K., Arbulo-Echevarria, M. et al. Identification of functional, short-lived isoform of linker for activation of T cells (LAT). Genes Immun 15, 449–456 (2014). https://doi.org/10.1038/gene.2014.35

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