alexa SAP-regulated T Cell-APC adhesion and ligation-dependent and -independent Ly108-CD3ζ interactions.


Journal of Clinical & Cellular Immunology

Author(s): Chu C, Wang Y, Zhang X, Ni X, Cao J,

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Abstract The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell-cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is required for stable cognate T-B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T-B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108-CD3ζ interactions. Constitutively associated with Src homology 2 domain-containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100-200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell-cell interactions, Ly108-CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108-CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T-B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell-APC interactions. Copyright © 2014 by The American Association of Immunologists, Inc. This article was published in J Immunol and referenced in Journal of Clinical & Cellular Immunology

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