Triggering of T cell proliferation through CD28 induces GATA-3 and promotes T helper type 2 differentiation in vitro and in vivo

Abstract

The relative contribution of T cell receptor-versus CD28-mediated signals in co-stimulation of resting CD4 T cells is thought to influence their functional differentiation towards T helper (Th) 1 versus Th2 subsets. We have used a conventional and a mitogenic CD28-specific monoclonal antibody to assess the effect of polyclonal T cell activation through CD28 alone on CD4 subset differentiation. In vivo, mitogenic but not conventional anti-CD28 induces massive lymphocytosis, the Th2 cytokines interleukin (IL)-4 and IL-10, and Th2-dependent immunoglobulin isotypes, most notably IgE. In vitro, it is shown that mitogenic anti-CD28 primes for IL-4-dependent induction of IL-4 expression much more efficiently than conventional co-stimulation. At the molecular level, we show for the first time that the activation of the "Th2 promoting" transcription factor GATA-3 requires co-stimulation by CD28 and is also induced by mitogenic anti-CD28 alone. We suggest that CD28-dependent induction of GATA-3 in concert with other transcription factors, which are preferentially induced by strong CD28-signals, primes CD4 T cells for IL-4-dependent Th2 differentiaton.

Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist

“…The present experiments were initiated because of our earlier observations that in vivo, the CD28 superagonist response is accompanied by high levels of IL-10 mRNA [33], and CD28-specific superagonistic mAb are highly effective in prevention and treatment of autoimmuneinflammatory rat models (unpublished results). As Treg cells are hyporesponsive to TCR stimulation with regard to proliferation [14], we therefore hypothesized that circumvention of TCR signaling with CD28 superagonists may provide a protocol for the expansion and activation of this subset.…”

“…Importantly, CD28 superagonists are also active in vivo, where in response to a single mAb injection, CD4 T cell numbers in peripheral lymphoid organs rise fivefold within 3 days before returning to base line levels [32]. Surprisingly, this dramatic polyclonal T cell response occurs without apparent inflammation or discomfort, a finding we have previously attributed to the strong induction of IL-10 but not of pro-inflammatory mediators during in vivo activation [33].…”

NF‐κB synergizes with NF‐AT and NF‐IL6 in activation of the IL‐4 gene in T cells

“…Accumulating evidence indicates that NF-‹ B may play an important role in activation of the IL-4 gene [12][13][14]. However, NF-‹ B was also shown to play an essential role in transcriptional expression of the Th2 transcription factor GATA-3 [17,18]. Therefore, the increased IL-4 production observed in p100 -/-mice [12] and default IL-4 expression observed in cRel -/-mice [14] might be solely due to an indirect effect of NF-‹ B via altered GATA-3 expression.…”

“…Although many studies indicate an important role of NF-‹ B in IL-4 gene expression, so far no study has yet shown that NF-‹ B interacts with the IL-4 promoter in vivo. Since NF-‹ B has also been implicated in transcriptional activation of the Th2-specific factor GATA-3 [17,18], the effect of NF-‹ B on IL-4 gene expression might be indirect through up-regulation of GATA-3. To determine whether NF-‹ B indeed bound to the IL-4 promoter in vivo, we performed chromatin immunoprecipitation (ChIP) assays.…”

Akt Is a Neutral Amplifier for Th Cell Differentiation

“…T cell costimulatory molecule CD28 plays a crucial role in the immune system in conjunction with T cell receptor signals, exerting positive effects on proliferation, cytokine production, and an anti-apoptotic effect in T cells, while suppressing anergy induction (2). Current models suggest that greater CD28 signal can achieve Th2 differentiation (6,7). An inducible costimulator, ICOS, also called H4 (8,9) or AILIM (10), is a member of the CD28 family and has roles similar to those of CD28 except for IL-2 production (11)(12)(13).…”