Humoral responses require a multi-stage T:B lymphocyte interaction process (99.5)

Abstract

Abstract X-linked lymphoproliferative (XLP) disease is an immune disorder caused by mutations encoding SLAM-associated protein (SAP, Sh2d1a), an adaptor that facilitates Fyn recruitment to SLAM family of receptors, including 2B4, Ly9, SLAM, CD84 and Ly108. SAP-/- CD4 T cells exhibit a selective impairment in adhesion to antigen presenting B cells but not dendritic cells (DC), resulting in defective germinal centre (GC) formation. However, the nature of this selective adhesion defect is unclear. We provide evidence that while T:DC interactions are primarily integrin-dependent, T:B cell interactions have an early integrin-dependent component and a sustained phase that also requires SAP. We further demonstrate that T cells adhere to the SLAM family members, CD84 and Ly108, in a SAP-dependent manner. Both CD84 and Ly108 are highly expressed on T follicular helper (TFH) cells, a specialized subset of CD4 T cells that reside within GCs and are critical for their formation. Cd84-/- mice exhibit a partial defect in GC responses to T-dependent antigens. This defect correlated with impaired cognate T:B cell conjugate pairing observed in vivo by dynamic imaging as well as reduced TFH cell differentiation and function. Strikingly, the combined loss of CD84 and Ly108 markedly reduced T:B conjugate pairing in vitro. Thus, our results identify SLAM family members as critical receptors involved in the dynamic regulation of sustained T:B cell interactions.