Induction of interleukin 4 (IL-4) expression in T helper (Th) cells is not dependent on IL-4 from non-Th cells.

Abstract

Interleukin 4 (IL-4) is essential for the induction of immunoglobulin E (IgE) responses in mice. Recent in vitro studies have suggested that IL-4 derived from non T helper (Th) cells, in particular from mast cells and basophils, may be essential for triggering of IL-4 expression in Th cells and may directly contribute to IgE isotype switch induction. Here, we have generated mice carrying a functional IL-4 gene only in Th cells or non-Th cells, respectively, by reconstitution of IL-4-deficient mice (IL-4T mice) with CD4+ or CD4- spleen cells from congenic wild-type animals. In mice in which only CD4+ cells are able to express IL-4, antigen-specific IgE is produced in a T cell-dependent immune response. Thus, induction of IL-4 expression in Th cells can occur in the absence of IL-4 from non-Th cells, which suggests that at least some Th cells can express IL-4 in response to another signal which has yet to be identified. No IgE is detectable, however, in mice in which only CD4- cells can express IL-4, suggesting that Th cells are the primary, if not the only source of IL-4 for initial induction of IgE synthesis.

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

“…1 and 4). Moreover, the IL-4 that plays this role is derived from newly activated naive CD4 T cells themselves, consistent with previous findings that IL-4 derived from T cells is sufficient for Th2 cell development (11,12). By inhibiting the early production of IL-4 by responding CD4 T cells, TLR-activated DCs undermine the Th2 development pathway and effectively prevent the outgrowth of this type of effector cell.…”

“…As a result, mice deficient in IL-4R or STAT6 fail to mount efficient Th2 responses (4). IL-4 produced by CD4 T cells is essential and sufficient for Th2 response development (11,12). Recent reports have shown that naive Th cells can rapidly produce IL-4 in response to TCR/ CD28 stimulation, and it is believed that this early IL-4, working in an autocrine fashion through a STAT6-dependent pathway, is critical for the up-regulation of GATA-3 expression and commitment to the Th2 lineage (13).…”

“…Taken together, these results indicate that IL-4 derived from CD4 T cells, but not DCs, is needed for Th2 cell development. CD4 T cells up-regulate both IL-4 and IFN-␥ production at early times postactivation with anti-CD3/anti-CD28, and IL-4 produced in this process is sufficient to drive Th2 cell development (11)(12)(13)18). We hypothesized that Pa-activated DCs might inhibit Th2 cell development by suppressing early IL-4 production by CD4 T cells.…”

Local Blockade of Allergic Airway Hyperreactivity and Inflammation by the Poxvirus-Derived Pan-CC-Chemokine Inhibitor vCCI

“…on day 14. Because Ͼ90% of protein allergenspecific IgE production by B cells and their plasma cell derivatives is dependent on IL-4 production by CD4 T cells (27), these results also suggest that vCCI treatment did not inhibit CD4 T cell activation, expansion, or Th2 differentiation in vivo. This was supported by studies demonstrating that OVA-stimulated bronchial lymph node T cells from vCCI-treated mice produced similar amounts of IL-4, IL-5, and IFN-␥ (Fig.…”

Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4+T cells

“…Initiation of Th2 differentiation is potentiated by IL-4 during encounter of naïve CD4 ϩ T cells with antigen, but the early source of IL-4 that is important for Th2 differentiation under physiological conditions is unclear (5). Although innate immune cells such as basophils and natural killer (NK) T cells can produce IL-4, it has been shown that Th2 cells can develop from naïve CD4 ϩ T cells independently of IL-4 produced by non-T cells (6). Naïve CD4 ϩ T cells themselves can produce small amounts of IL-4 after antigen stimulation, which is sufficient for Th2 differentiation under certain conditions (7).…”