CD40 ligand signals optimize T helper cell cytokine production: role in Th2 development and induction of germinal centers

Abstract

The role of CD40 in the development of germinal centers (GC) is not simply to initiate the B cell response, as rudimentary GC can develop in CD40 −/− mice that are injected with CD40-immunoglobulin (Ig) fusion protein. This indicates that CD40 ligand (CD40L) transduces a signal to T cells that is important in the process. In this study we have used an in vitro model of GC development to investigate the role of CD40L, cytokines and other co-stimuli. The model involves the specific induction of an H-2E transgene in GC B cells (in Sma58 mice). We find that Th2 cytokines together with Ig and CD40 cross-linking are the most efficient means of induction of the GC phenotype. Although IL-4 plays some inductive role, it is not the sole active ingredient in the mix of cytokines made by Th2 cells. Our studies on primary T cells and T cell clones activated in the absence of CD40 on antigen-presenting cells or CD40L on T cells indicate that the CD40L co-stimulus does not directly bias the response to Th2 cells, as previously reported, but that it augments terminal effector T cell differentiation or the level of secretory activity. However, both in vitro and in vivo, the CD40L co-stimulus is crucially important for Th2 development as in its absence IL-4 production is suboptimal and does not compete with a larger, more rapid IFN-+ response.

Th1 and Th2 CD4+ T Cells Provide Help for B Cell Clonal Expansion and Antibody Synthesis in a Similar Manner In Vivo

“…Our findings contrast with recent studies (21,39), which suggested that, unlike Th2 cells, Th1 cells localize in the paracortex by virtue of their expression of CCR7 and are unable to support the differentiation of naive B cells into germinal center cells. These results do not explain the production of high-affinity IgG2a-secreting B cells that develop with the help of Th1-derived cytokines such as IFN-␥.…”

“…Although early in vitro studies indicated that both Th1 and Th2 cells could support B cell responses (15)(16)(17), the capacity of Th1 cells to provide cognate help for B cells is controversial, with some studies reporting that they are relatively deficient in this function (21,39,40). However, care must be taken when interpreting such in vitro studies, as examination of several Th1 and Th2 clones revealed considerable variation in their ability to help B cells with some Th2 clones failing to support Ab synthesis at all (15).…”

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

“…Confirming in vitro data, OVA-specific T reg proliferate 50% less when transferred into CD40KO mice than into wt mice exposed to OVA immunization. CD40L costimulation has been shown to promote the terminal differentiation and cytokines secretion of CD4 + T cells [24,25]. T reg proliferation does not occur via triggering of CD40L since B cells that constitutively express high level of CD40 cannot substitute DC in inducing T reg proliferation (data not shown).…”

Mechanisms of tolerance induction: blockade of co–stimulation

“…Whether and how CD40L cross-linking a¡ects T-cell functions is less well documented, but it has been demonstrated to contribute to the development of helper function (Van Essen et al 1995), to enhance cytokine production and to give rise to terminal T-cell di¡erenti-ation in vitro (Poudrier et al 1998).…”