5,9,16,35,36 Once again, a range of cell surface receptors interactions play an important role at this stage. As for DC–T interactions, CD40–CD40L are also important for T–B interactions, as a lack of CD40 expression on B cell prevents activation of B cells by T cells which, in turn, results in decreased Tfh cell numbers.15 In contrast, while CD28 seems to be important at the initial stages of CD4+ T cell activation it
selleck chemicals llc does not seem to be as crucial for Tfh cell development at the later stages of T–B interactions.37,38 A recent study, however, reported that B7.2 expression on B cells was required for GC formation, suggesting the B7–CD28 interactions between T–B cells are important for the function of Tfh cells and the delivery of helper signals to the B cells.39 For the most part, however, another CD28 family member, namely ICOS, seems to be required at this later stage. Consequently, mice in which ICOS–ICOSL interactions are
disrupted, or patients with mutations in ICOS (which results in common variable immunodeficiency), have decreased Tfh cells.26,32,40,41 ICOSL is expressed widely on haematopoietic cells; however, mice that lack ICOSL expression on their B cells show decreased numbers of Tfh cells indicating that, at least in part, this ICOS–ICOSL signal is delivered by B cells.42 This requirement for ICOS signalling seems Selleckchem Cilomilast to depend on its ability to activate phosphoinositide-3-kinase (PI3K), as mice expressing a mutant ICOS molecule with defective PI3K activation41 or lacking the p110δ isoform of PI3K in T cells43 also show decreased Tfh cell generation. Several studies have demonstrated that ICOS signalling, via PI3K, is able to up-regulate Tfh cell-associated genes such as c-maf,
IL-4 and IL-21;40,41,43 however, it remains to be determined whether the primary role of ICOS signalling is to induce the differentiation of Tfh cells or simply to maintain those that have already formed. It Buspirone HCl has also become clear that the SLAM family of surface receptors play an important role in Tfh cell generation. The importance of these molecules in T–B interactions first came to light in patients suffering from the immunodeficiency X-linked lymphoproliferative disease (XLP). XLP is caused by mutations in the gene encoding SAP (i.e. SH2D1A), which is a cytoplasmic adaptor molecule that signals downstream of the SLAM family of receptors. Patients with XLP, as well as gene-targeted mice that lack SAP expression, display a deficiency in T-dependent B cell responses.44,45 Furthermore, several groups have demonstrated that loss of SAP can result in decreased numbers of Tfh cells.9,20,46,47 Members of the SLAM family including SLAM itself, CD84 and NTBA (also known as Ly108 in the mouse) are expressed highly on both activated B cells and activated CD4+ T cells, including Tfh cells.8,9,11,20,47–50 As these receptors are homotypic receptors, this expression pattern allows for SLAM family interactions between T and B cells.