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Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms

Nature Immunology volume 3, pages 764–771 (2002)Cite this article

Abstract

The regulation of receptor-like protein tyrosine phosphatases (RPTPs) is not well understood. Although CD45 can be negatively regulated by dimerization, how dimerization is modulated is unclear. Here we show that various isoforms of CD45 differentially homodimerize in T cells. The dimerization is modulated by the sialylation and O-glycosylation of alternatively spliced CD45 exons in the extracellular domain. Thus, the smallest isoform, CD45RO—which undergoes the least extracellular sialylation and O-glycosylation—homodimerizes with the highest efficiency, resulting in decreased signaling via the T cell receptor. Because CD45 is required for T cell activation, our findings may reveal a mechanism that contributes to the termination of the primary T cell response. Our results not only demonstrate the biological significance of alternative splicing in the immune system, but also suggest a model for regulating RPTP dimerization and function.

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Figure 1: Differential dimerization of CD45 isoforms in human peripheral T cells.
Figure 2: Differential homodimerization of CD45 isoforms in transfected T cells.
Figure 3: More efficient and rapid dimerization of CD45RO than CD45RABC.
Figure 4: Dimerization of CD45 independent of its intracellular domain.
Figure 5: Modulation of CD45 dimerization by the sialylation and O-glycosylation of the alternatively spliced exons in the extracellular domain.
Figure 6: Regulation of TCR signaling by isoform-differential homodimerization of CD45.
Figure 7: Wedge-dependent negative regulation of CD45 by dimerization.

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Acknowledgements

We thank the late M. Thomas for murine CD45RO and CD45RABC cDNA; L. Lanier for the mAb UCHL-1 to human RO and FITC-labeled mAb L48 to human RA; P. Johnson for RO2.2 antiserum to murine CD45; M. Krieger and S. Rosen for ldlD cells; S. M. Fu for mAb 235 to CD3; B. Schraven for LPAP antiserum; M. Hermiston for critical reading of this manuscript; and T. Meyer, K. Lynch, J. Liou and members of the Weiss lab for helpful discussions. Supported by NIH grants GM39553 and AI35297 (to A. W.) and the Rosalind Russell Medical Research Center for Arthritis.

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  1. Departments of Medicine and of Microbiology and Immunology and the Howard Hughes Medical Institute, University of California, San Francisco, 94143-0795, CA, USA

    Zheng Xu & Arthur Weiss

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Correspondence to Arthur Weiss.

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Xu, Z., Weiss, A. Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nat Immunol 3, 764–771 (2002). https://doi.org/10.1038/ni822

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