Triggering of T cell proliferation through CD28 induces GATA‐3 and promotes T helper type 2 differentiation<i>in vitro</i>and<i>in vivo</i>

Rodrı́guez-Palmero, Marı́a; Hara, Toyomichi; Thumbs, Alexander; Hünig, Thomas

doi:10.1002/(sici)1521-4141(199912)29:12<3914::aid-immu3914>3.0.co;2-#

Cited by 100 publications

(6 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This might be explained by the observation that at least during thymic development GATA-3 expression raises during stages of high proliferation (45). Moreover, it has been reported that a polyclonal stimulation of CD4 + T cells increases GATA-3 expression (46). Hence, under the influence of ConA DON may again increase further the expression of a transcription factor, which is already induced by the polyclonal stimulation of the T cells in the PBMC-cultures.…”

Section: Discussionmentioning

confidence: 99%

Deoxynivalenol Has the Capacity to Increase Transcription Factor Expression and Cytokine Production in Porcine T Cells

et al. 2020

View full text Add to dashboard Cite

Deoxynivalenol (DON) is a Fusarium mycotoxin that frequently contaminates the feed of farm animals. Pigs with their monogastric digestive system are in particular sensitive to DON-contaminated feed. At high concentrations, DON causes acute toxic effects, whereas lower concentrations lead to more subtle changes in the metabolism. This applies in particular to the immune system, for which immunosuppressive but also immunostimulatory phenomena have been described. Research in human and rodent cell lines indicates that this may be partially explained by a binding of DON to the ribosome and subsequent influences on cell signaling molecules like mitogen-activated protein kinases. However, a detailed understanding of the influence of DON on functional traits of porcine immune cells is still lacking. In this study, we investigated the influence of DON on transcription factor expression and cytokine production within CD4 + , CD8 + , and γδ T cells in vitro. At a DON concentration, that already negatively affects proliferation after Concanavalin A stimulation (0.8 µM) an increase of T-bet expression in CD4 + and CD8 + T cells was observed. This increase in T-bet expression coincided with elevated levels of IFN-γ and TNF-α producing T-cell populations. Increases in T-bet expression and cytokine production were found in proliferating and non-proliferating T cells, although increases were more prominent in proliferating cell subsets. Differently, IL-17A production by CD4 + T cells was not influenced by DON. In addition, frequencies of regulatory T cells and their expression of Foxp3 were not affected. In γδ T cells, GATA-3 expression was slightly reduced by DON, whereas T-bet levels were only slightly modulated and hence IFN-γ, TNF-α, or IL-17A production were not affected. Our results show for the single-cell level that DON has the capacity to modulate the expression of transcription factors and related cytokines. In particular, they suggest that for CD4 + and CD8 + T cells, DON can drive T-cell differentiation into a pro-inflammatory type-1 direction, probably depending on the already prevailing cytokine milieu. This could have beneficial or detrimental effects in ongoing immune responses to infection or vaccination.

show abstract

Section: Discussionmentioning

confidence: 99%

Deoxynivalenol Has the Capacity to Increase Transcription Factor Expression and Cytokine Production in Porcine T Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Previously it has been reported that CD28-costimulation induces GATA3 expression and Th2 differentiation via the activation of NFκB [41,42]. Additional studies in mice revealed that PKCθ is involved in mounting both Th2- and Th1-mediated lung inflammation, although Th2-mediated inflammation is more PKCθ-dependent [43].…”

Section: Discussionmentioning

confidence: 99%

Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

Smeets

Fleuren

et al. 2012

BMC Immunol

View full text Add to dashboard Cite

BackgroundT lymphocytes are orchestrators of adaptive immunity. Naïve T cells may differentiate into Th1, Th2, Th17 or iTreg phenotypes, depending on environmental co-stimulatory signals. To identify genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli and pathway inhibitors. Results from these experiments were validated in a human experimental setting using whole blood and purified CD4+ Tcells.ResultsCalcium-dependent activation of T cells using CD3/CD28 and PMA/CD3 stimulation induced a Th1 expression profile reflected by increased expression of T-bet, RUNX3, IL-2, and IFNγ, whereas calcium-independent activation via PMA/CD28 induced a Th2 expression profile which included GATA3, RXRA, CCL1 and Itk. Knock down with siRNA and gene expression profiling in the presence of selective kinase inhibitors showed that proximal kinases Lck and PKCθ are crucial signaling hubs during T helper cell activation, revealing a clear role for Lck in Th1 development and for PKCθ in both Th1 and Th2 development. Medial signaling via MAPkinases appeared to be less important in these pathways, since specific inhibitors of these kinases displayed a minor effect on gene expression. Translation towards a primary, whole blood setting and purified human CD4+ T cells revealed that PMA/CD3 stimulation induced a more pronounced Th1 specific, Lck and PKCθ dependent IFNγ production, whereas PMA/CD28 induced Th2 specific IL-5 and IL-13 production, independent of Lck activation. PMA/CD3-mediated skewing towards a Th1 phenotype was also reflected in mRNA expression of the master transcription factor Tbet, whereas PMA/CD28-mediated stimulation enhanced GATA3 mRNA expression in primary human CD4+ Tcells.ConclusionsThis study identifies stimulatory pathways and gene expression profiles for in vitro skewing of T helper cell activation. PMA/CD3 stimulation enhances a Th1-like response in an Lck and PKCθ dependent fashion, whereas PMA/CD28 stimulation results in a Th2-like phenotype independent of the proximal TCR-tyrosine kinase Lck. This approach offers a robust and fast translational in vitro system for skewed T helper cell responses in Jurkat T cells, primary human CD4+ Tcells and in a more complex matrix such as human whole blood.

show abstract

“…This correlation between function and topology of binding was observed in rats, mice, and humans [12, 20]. In rodents, CD28 superagonists induce immune deviation to Th2 [22] as well as expansion and functional activation of “natural” Treg cells [23–25]. Accordingly, such mAb have high therapeutic efficacy in a wide range of rodent models of autoimmunity, inflammation, and allograft rejection [25–31].…”

Section: Immune Deviation and Treg Activation With Stimulatory Cd28-smentioning

confidence: 94%

“…In this model of African trypanosomiasis, CD28SA treatment down-regulated IFNγ and TNF production by T-cells along with the production of reactive oxygen species by classically activated macrophages. Interestingly, it also triggered the development of alternatively activated macrophages, in line with a CD28SA-induced Th2 shift and IL-4 production [22]. With regard to pathology, CD28SA treatment delayed the onset of liver injury, diminished the anemia burden, and prolonged the survival of infected animals.…”

Section: Immune Deviation and Treg Activation With Stimulatory Cd28-smentioning

confidence: 99%

CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation

Hünig

Lühder

Elflein

et al. 2010

Med Microbiol Immunol

Self Cite

View full text Add to dashboard Cite

The costimulatory receptor CD28 and IL-4Rα-containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Rα signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore, immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Rα and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Rα in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.

show abstract

Triggering of T cell proliferation through CD28 induces GATA‐3 and promotes T helper type 2 differentiationin vitroandin vivo

Cited by 100 publications

References 46 publications

Deoxynivalenol Has the Capacity to Increase Transcription Factor Expression and Cytokine Production in Porcine T Cells

Deoxynivalenol Has the Capacity to Increase Transcription Factor Expression and Cytokine Production in Porcine T Cells

Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling

CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation

Contact Info

Product

Resources

About