The secondary humoral immune response is characterized by plasma B cells secreting isotype-switched and affinity-matured antibodies. The efficient generation of plasma B cells in the GC depends on the presence of follicular helper T (T(FH)) cells, a cell type thought to arise from naive CD4-positive T cells by a hitherto unresolved differentiation pathway. Mice deficient for CD155, an adhesion receptor of the immunoglobulin superfamily, are impaired to mount a secondary humoral immune response upon oral administration of antigen, while the primary IgM response is unaffected. Here, we show that mice lacking CD155 harbor significantly reduced numbers of T(FH) cells in their Peyer's patches. This was paralleled by a decreased frequency of T(FH) cells in the GC. Moreover, the CD155 ligand CD226, which is involved in T-cell activation, is down-regulated during T(FH) cell differentiation, resulting in a complete absence of CD226 on those T(FH) cells residing in the GC. Concurrently, the expression of TIGIT/WUCAM, a newly discovered CD155 ligand, is induced in T(FH) cells. Thus, these cells replace an activating by a putative inhibitory CD155-binding partner during their differentiation.