SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

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.

Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8

“…So, we reasoned that IRF8 might promote the antigen-specific interaction of FO B cells with their helper T cell counterparts. Consistent with our hypothesis, the interaction of ovalbumin peptide-loaded Irf8 −/− FO B cells with activated OT-II T cells (which have transgenic expression of an ovalbumin-specific T cell antigen receptor) was significantly compromised, as measured by a flow cytometry-based cell-conjugate assay 26 (Fig. 3h).…”

Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production

“…The role of SAP in the expression of autoimmunity and in T cell activation and function is unclear (38) (39) (40) (25). Studies have claimed that SAP activates CD3ζ chain and other canonical T cell signaling molecules (40).…”

TFH cells in bystander and cognate interactions with B cells

“…67 Subsequent live-imaging investigation has led us to realize that such interactions begin in the form of long-lasting monogamous pairs at the T-B border, 16 driven by antigen receptor signaling that is modulated by SAP-dependent pathways, 17,68,69 and becoming progressively shortened in duration as such interactions evolve into the follicular phase. 67 Subsequent live-imaging investigation has led us to realize that such interactions begin in the form of long-lasting monogamous pairs at the T-B border, 16 driven by antigen receptor signaling that is modulated by SAP-dependent pathways, 17,68,69 and becoming progressively shortened in duration as such interactions evolve into the follicular phase.…”