SLAM-associated protein (SAP)-deficiency impedes the function of T follicular helper cells in germinal center formation (99.3)

Abstract

Abstract Mutations affecting SAP lead to XLP, an immune disorder with impaired antibody responses. SAP-/- mice show defective formation of germinal centers (GC), due to a defect in T:B cell interactions. T follicular helper cells (Tfh) are important for providing help to B cells and GC formation. To investigate the role of SAP in Tfh cells for GC formation, we have developed a modified protocol to generate “Tfh-like” cells in vitro, resulting in IL-21 producing cells with elevated expression of hallmark Tfh markers CXCR5, ICOS, PD-1, BTLA, and SLAM family receptors CD84 and Ly108, along with enhanced levels of Bcl6 transcripts. Cell transfer of control Tfh-like cells into SAP-/- hosts can rescue GC formation upon immunization significantly better than polarized Th1, Th2 or Th17 cells, suggesting these cells act as functional Tfh cells in vivo. In vitro differentiation of SAP-/- cells is similar to control cells, yet, upon cell transfer, SAP-/- Tfh-like cells are unable to support GC formation. Interestingly, differentiation of Tfh-like cells is not terminal, as they can be repolarized to produce other distinct Th cell cytokines. Similarly, other Th cell populations can be repolarized to Tfh-like cells. Analyses of epigenetic modifications of transcription factors also supports plasticity between these Th cell lineages. These findings provide further insight into Tfh cell biology and suggest that SAP is critical for Tfh cell function in GC formation and immune homeostasis.