Co-activation of naive CD4⁺ T cells and bone marrow-derived mast cells results in the development of T_h2 cells

Abstract

Activation of naive dense CD4+ T cells by plate-bound anti-CD3 antibodies favors the development of Th1 cells which, upon re-stimulation, produce significant amounts of IFN-gamma but no IL-4. However, co-activation of such naive T cells in the presence of IgE [anti-dinitrophenyl (DNP)]-loaded bone marrow-derived mast cells (BMMC) on plates coated with anti-CD3 antibodies and DNP-BSA led to the development of IL-4-producing Th2 cells. The same result could be observed if irradiated (800 rad) BMMC were applied as co-stimulators. Moreover, BMMC could be replaced by the supernatant of IgE-activated BMMC suggesting that a soluble mediator, presumably IL-4, was responsible for this effect. This assumption was substantiated using neutralizing anti-IL-4 antibodies which abolished the BMMC-mediated Th2 development in all cases. Addition of IL-12, a cytokine that was shown to antagonize the Th2-promoting effect of IL-4 in vivo, could not inhibit the development of IL-4-producing T cells, but gave rise to a T cell population which produced relatively high amounts of IL-4 and IFN-gamma. Since BMMC represent the in vitro equivalent of mucosal mast cells these data suggest that IgE-activated mucosal mast cells can bias an emerging T cell dependent immune response towards a Th2 dominated reaction by the initial production of IL-4.

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

“…Mast cell-derived cytokines have numerous effects on other cells of the immune system as well as endothelial cells. For example, mast cell-derived cytokines can cause B cells to class switch to synthesize IgE, induce basophil histamine release, recruit neutrophils and eosinophils, and promote the development of T cells into a T helper 2 (Th2) phenotype [17][18][19].…”

“…In addition to the effects mast cells directly exert on the pathogenesis of asthma, they also have the ability to contribute to the initiation of Th2 responses by the production of IL-4 and IL-13 [18]. Recently, thymic stromal lymphopoietin (TSLP), released by epithelial cells in response to physical injury and/or inflammatory cytokines, has been reported as a possible initiator of asthmatic responses through the potent stimulation of mast cells, to produce high levels of Th2 cytokines [51].…”

Mast Cell Migration from the Skin to the Draining Lymph Nodes upon Ultraviolet Irradiation Represents a Key Step in the Induction of Immune Suppression

“…During the early phase (i.e., within hours of UV exposure) an IL-10-producing suppressor B cell is activated (18,19), followed a few days to weeks later by CD4 ϩ regulatory T cells (4,20,21). Mast cells are not only potent B cell activators (22,23), they are capable of producing Th2-polarizing cytokines (24) that preferentially activate CD4 ϩ Th2 cells (25). Most of these earlier studies used in vitro-cultured BMMC and therefore it is still not clear exactly how a mast cell in the periphery influences lymphocyte activation, although their ability to reach draining lymph nodes (DLN) where lymphocyte activation occurs would seem to be a necessary prerequisite.…”

Cell-cell cooperation at the T helper cell/mast cell immunological synapse

“…6,7 In turn, it has been shown that activated T cells can induce in vitro histamine, TNF-␣, matrix metalloproteinase-9 secretion, and interleukin 4 (IL-4) mRNA expression in mast cell subsets. [16][17][18] Finally, mast cells have been reported to promote in vivo T-cell migration to inflammatory sites by secreting chemotactic factors, such as lymphotactin and IL-16 19 and to orient Th differentiation via the production of 21 Taken together these studies highlight the existence of functionally important mast cell/T-cell crosstalk and raise the question of whether mast cell/T-cell cognate interactions might occur in the course of immune responses.Immunological synapses (ISs) are the morphologic manifestation of the cognate interactions occurring between T cells and other cells of the immune system serving as antigen-presenting cells (APCs). These specialized areas of signal transduction, formed at the T cell/APC contact site, are characterized by large scale clustering and segregation of surface molecules and intracellular signaling components.…”