Thus, in the absence of SAP or CD84, CD4+ T cells are unable to form stable conjugates with B cells and cannot deliver help to B cells.47,51 In addition, this prevents the CD4+ T cells from receiving signals from B cells that regulate the formation or maintenance of Tfh cells. While

it is thought that Tfh cell development is a multi-step process with initial activation on DCs, followed by secondary signals provided by B cells, several recent findings have challenged this view. Many reports have demonstrated that Tfh cell numbers are decreased in the absence of B cells or when T–B cell interactions are disrupted.5,9,16,35,36 However, we recently showed that in the absence of antigen presentation by B cells, Tfh cell development (as indicated by surface phenotype and GC localization) could at least partially be CHIR-99021 ic50 rescued in the presence of abundant antigen, which prolonged presentation by DCs.9 Consistent with this, a recent study found that mTOR inhibitor Tfh cells also developed in B cell-deficient mice in response

to chronic viral infection.52 This suggests that the requirement for B cells results not from a unique signal that B cells provide, but because Tfh cells need prolonged antigen stimulation and B cells often quickly become the only cells capable of presenting antigen to the T cells.9 A requirement for prolonged antigen presentation is consistent with data indicating a crucial role of TCR signalling in Tfh cell development. For example, many of the features of Tfh cells, such as up-regulation of CXCR5 and PD-1 and down-regulation of CD127, are observed in T cells following TCR stimulation.3,6,53,54 Moreover, it has been shown that high-affinity Cytidine deaminase T cells are preferentially selected to become Tfh cells.55 The restriction of antigen presentation to the B cells presumably occurs ordinarily because, first, the B cell receptor allows for efficient uptake of antigen and secondly, as the T cells move

into the B cell follicle and then the GC, these are the antigen-presenting cells (APCs) which the T cells encounter. Furthermore, several new papers support the idea that early activation on DCs is able to drive differentiation of Tfh cells. They demonstrated that CD4+ T cells with a Tfh cell phenotype – high CXCR5, PD1, IL-21 and Bcl-6 expression – could be identified early on in the response (e.g. day 3)21–23 in the interfollicular zone or outer follicle.21,22 This early appearance of Tfh-like cells was independent of B cells;21,23 however, the continued maintenance of these cells was disrupted in the absence of B cells.21–23 This suggests that a role of the second round of signalling, usually provided by B cells, may be to maintain a Tfh cell phenotype or the survival of Tfh cells rather than to drive unique differentiation events. Generation of the different Th lineages is associated with the action of particular cytokines.