SAP-controlled T-B cell interactions underlie germinal centre formation

Nature. 2008 Oct 9;455(7214):764-9. doi: 10.1038/nature07345.


Generation of long-term antibody-mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen-specific T and B lymphocytes. In human X-linked lymphoproliferative disease and its gene-targeted mouse model, loss-of-function mutations in signalling lymphocyte activation molecule-associated protein (SAP, encoded by SH2D1a) cause a profound defect in germinal centre formation by an as yet unknown mechanism. Here, using two-photon intravital imaging, we show that SAP deficiency selectively impairs the ability of CD4(+) T cells to stably interact with cognate B cells but not antigen-presenting dendritic cells. This selective defect results in a failure of antigen-specific B cells to receive adequate levels of contact-dependent T-cell help to expand normally, despite Sap(-/-) T cells exhibiting the known characteristics of otherwise competent helper T cells. Furthermore, the lack of stable interactions with B cells renders Sap(-/-) T cells unable to be efficiently recruited to and retained in a nascent germinal centre to sustain the germinal centre reaction. These results offer an explanation for the germinal centre defect due to SAP deficiency and provide new insights into the bi-directional communication between cognate T and B cells in vivo.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Adhesion
  • Cell Communication
  • Cells, Cultured
  • Chimera / immunology
  • Dendritic Cells / immunology
  • Germinal Center / cytology*
  • Germinal Center / immunology*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation
  • Mice
  • Signaling Lymphocytic Activation Molecule Associated Protein


  • Intracellular Signaling Peptides and Proteins
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein