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Overexpression of CD45RA isoforms in carriers of the C77G mutation leads to hyporeactivity of CD4+CD25highFoxp3+ regulatory T cells

Genes & Immunity volume 16, pages 519–527 (2015)Cite this article

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Abstract

Disorders in regulatory T-cell (Treg) function can result in the breakdown of immunological self-tolerance. Thus, the identification of mechanisms controlling the activity of Treg is of great relevance. We used Treg from individuals carrying the C77G polymorphism as models to study the role of CD45 molecules in humans. C77G prevents splicing of CD45 exon A thereby leading to an aberrant expression pattern of CD45 isoforms in affected individuals. Resting and in vitro expanded/activated CD4+CD25highFoxp3+ Treg from carriers of C77G strongly expressed CD45RA isoforms whereas these isoforms were almost absent in cells from individuals with wild-type CD45. C77G Treg showed diminished upregulation of activation markers, lower phosphorylation of p56lck(Y505) and a reduced proliferative potential when stimulated with anti-TcR or anti-TcR plus CD28 mAb suggesting decreased responsiveness to activating stimuli. In addition, the capacity to suppress proliferation of conventional CD4+ T cells was impaired in C77G Treg. Furthermore, microarray studies revealed distinct gene expression patterns in Treg from C77G carriers. These data suggest that the changes in CD45 isoform combination resulting from the C77G mutation alter the responsiveness of Treg to TcR-mediated signaling. Targeting CD45 isoform expression might be a useful approach to modulate Treg function.

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Acknowledgements

We acknowledge the assistance of the Cell Sorting Core Facility of Hannover Medical School, which is supported in part by Braukmann-Wittenberg-Herz-Stiftung and Deutsche Forschungsgemeinschaft. We thank Dr Penelope Kay-Fedorov for her constructive comments on the manuscript. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (Schw437/2 and SFB 738).

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  1. Department of General, Transplant Laboratory, Visceral, and Transplantation Surgery, Hannover Medical School, Hannover, Germany

    C Pokoyski, T Lienen, S Rother, E Schock, A Plege-Fleck & R Schwinzer

  2. Research Group Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany

    R Geffers

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  1. C Pokoyski
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Correspondence to R Schwinzer.

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Pokoyski, C., Lienen, T., Rother, S. et al. Overexpression of CD45RA isoforms in carriers of the C77G mutation leads to hyporeactivity of CD4+CD25highFoxp3+ regulatory T cells. Genes Immun 16, 519–527 (2015). https://doi.org/10.1038/gene.2015.39

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