Wild-type CD4+ T cells (black circles), but not SAP-deficient CD4+ T cells (closed squares), restore antibody production in SAP-deficient mice.

The absence of SAP wreaks havoc on the immune system. SAP—the adaptor that links the SLAM family of activating receptors to the downstream signaling protein Fyn—is expressed in most immune cell types and its absence causes a bevy of immune defects.

Mutations in SAP cause a rare disease called X-linked lymphoproliferative disease (XLP), which is characterized in part by extreme susceptibility to Epstein Barr virus (EBV) infection. Those who survive EBV infection often have long-term antibody deficiencies. But Cannons and colleagues put the blame for this not on B cells, but on CD4⁺ T cells.

Previous studies in SAP-deficient mice revealed defects in both CD4⁺ T cells and B cells. But whether one cell type is mostly to blame for the glitch in antibody production has been controversial. Here, Cannons and colleagues put the rap squarely on the CD4⁺ T cells, as transfer of wild-type T cells into SAP-deficient mice restored immunization-induced antibody production, even when the B cells still lacked the adaptor.

The authors suspected (based on previous work with SAP-deficient T cells) that SAP-deficient mice might be unable to secrete antibody-promoting Th2 cytokines, such as interleukin (IL)-4 and IL-10. But when they infected the mice with Shistosoma mansonii eggs—a classic Th2 trigger—the mice had no problem producing these cytokines. Antibody production, on the other hand, was still blocked.

The antibody defect was instead traced to changes in the expression of two T cell costimulatory molecules: CD40 ligand (CD40L) and ICOS. In SAP-deficient cells, CD40L expression was increased and ICOS expression was decreased—both changes that have been shown to inhibit antibody production. A decrease in ICOS expression has also been reported on T cells from patients with XLP.

SAP's ability to bind Fyn was dispensable for antibody production, as T cells containing a Fyn binding mutant of SAP still restored antibody production in mutant mice. The authors are now characterizing this previously unrecognized signaling pathway.