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The acute environment, rather than T cell subset pre-commitment, regulates expression of the human T cell cytokine amphiregulin.

Qi Y, Operario DJ, Georas SN, Mosmann TR - PLoS ONE (2012)

Bottom Line: Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals.Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines.This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses.

View Article: PubMed Central - PubMed

Affiliation: David H Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.

ABSTRACT
Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals. We showed previously that the epidermal growth factor family member Amphiregulin is expressed by T cell receptor-activated mouse CD4 T cells, particularly Th2 cells, and helps eliminate helminth infection. Here we report a detailed analysis of the regulation of Amphiregulin expression by human T cell subsets. Signaling through the T cell receptor induced Amphiregulin expression by most or all T cell subsets in human peripheral blood, including naive and memory CD4 and CD8 T cells, Th1 and Th2 in vitro T cell lines, and subsets of memory CD4 T cells expressing several different chemokine receptors and cytokines. In these different T cell types, Amphiregulin synthesis was inhibited by an antagonist of protein kinase A, a downstream component of the cAMP signaling pathway, and enhanced by ligands that increased cAMP or directly activated protein kinase A. Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines. Thus, in contrast to mouse T cells, Amphiregulin synthesis by human T cells is regulated more by acute signals than pre-commitment of T cells to a particular cytokine pattern. This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses.

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Related in: MedlinePlus

Release of AR from the T cell surface was blocked by the ADAM17 inhibitor TAPI-1.(A) PBMC were stimulated with SEB in the presence or absence of TAPI-1 for variable times. After cell surface staining of AR, the percentage of CD69+AR+ cells within CD4 and CD8 T cells was analyzed. (B) Purified CD4 T cells were treated with medium alone or anti-CD3/CD28 beads with or without TAPI-1 for 24 hours. The concentration of AR in the supernatant was measured by ELISA. All results are representative of at least three experiments.
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pone-0039072-g003: Release of AR from the T cell surface was blocked by the ADAM17 inhibitor TAPI-1.(A) PBMC were stimulated with SEB in the presence or absence of TAPI-1 for variable times. After cell surface staining of AR, the percentage of CD69+AR+ cells within CD4 and CD8 T cells was analyzed. (B) Purified CD4 T cells were treated with medium alone or anti-CD3/CD28 beads with or without TAPI-1 for 24 hours. The concentration of AR in the supernatant was measured by ELISA. All results are representative of at least three experiments.

Mentions: EGF family members (including AR) are initially expressed as transmembrane proteins and released into the extracellular region after cleavage by metalloproteases, particularly ADAM17 [22]. To determine whether T cells also initially expressed surface AR and then released the soluble cleavage product, surface AR was stained during TCR activation in the presence or absence of the ADAM17/TACE inhibitor TAPI-1 [32]. TAPI-1 increased AR expression on the surface of both CD4 and CD8 T cells measured by frequency (Figure 3A) or fluorescence intensity (data not shown). Conversely, TAPI-1 decreased soluble AR in the supernatant (Figure 3B). In the absence of TAPI-1, AR expression on T cells gradually decreased and was barely detectable after 24 hours. As ADAM17 mRNA was detected by RT-PCR in resting human T cells and upregulated on activation (data not shown), these results suggested that AR was first synthesized as a membrane protein on human T cells and then released by ADAM17 cleavage, as in other cell types [34], [35].


The acute environment, rather than T cell subset pre-commitment, regulates expression of the human T cell cytokine amphiregulin.

Qi Y, Operario DJ, Georas SN, Mosmann TR - PLoS ONE (2012)

Release of AR from the T cell surface was blocked by the ADAM17 inhibitor TAPI-1.(A) PBMC were stimulated with SEB in the presence or absence of TAPI-1 for variable times. After cell surface staining of AR, the percentage of CD69+AR+ cells within CD4 and CD8 T cells was analyzed. (B) Purified CD4 T cells were treated with medium alone or anti-CD3/CD28 beads with or without TAPI-1 for 24 hours. The concentration of AR in the supernatant was measured by ELISA. All results are representative of at least three experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375254&req=5

pone-0039072-g003: Release of AR from the T cell surface was blocked by the ADAM17 inhibitor TAPI-1.(A) PBMC were stimulated with SEB in the presence or absence of TAPI-1 for variable times. After cell surface staining of AR, the percentage of CD69+AR+ cells within CD4 and CD8 T cells was analyzed. (B) Purified CD4 T cells were treated with medium alone or anti-CD3/CD28 beads with or without TAPI-1 for 24 hours. The concentration of AR in the supernatant was measured by ELISA. All results are representative of at least three experiments.
Mentions: EGF family members (including AR) are initially expressed as transmembrane proteins and released into the extracellular region after cleavage by metalloproteases, particularly ADAM17 [22]. To determine whether T cells also initially expressed surface AR and then released the soluble cleavage product, surface AR was stained during TCR activation in the presence or absence of the ADAM17/TACE inhibitor TAPI-1 [32]. TAPI-1 increased AR expression on the surface of both CD4 and CD8 T cells measured by frequency (Figure 3A) or fluorescence intensity (data not shown). Conversely, TAPI-1 decreased soluble AR in the supernatant (Figure 3B). In the absence of TAPI-1, AR expression on T cells gradually decreased and was barely detectable after 24 hours. As ADAM17 mRNA was detected by RT-PCR in resting human T cells and upregulated on activation (data not shown), these results suggested that AR was first synthesized as a membrane protein on human T cells and then released by ADAM17 cleavage, as in other cell types [34], [35].

Bottom Line: Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals.Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines.This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses.

View Article: PubMed Central - PubMed

Affiliation: David H Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.

ABSTRACT
Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals. We showed previously that the epidermal growth factor family member Amphiregulin is expressed by T cell receptor-activated mouse CD4 T cells, particularly Th2 cells, and helps eliminate helminth infection. Here we report a detailed analysis of the regulation of Amphiregulin expression by human T cell subsets. Signaling through the T cell receptor induced Amphiregulin expression by most or all T cell subsets in human peripheral blood, including naive and memory CD4 and CD8 T cells, Th1 and Th2 in vitro T cell lines, and subsets of memory CD4 T cells expressing several different chemokine receptors and cytokines. In these different T cell types, Amphiregulin synthesis was inhibited by an antagonist of protein kinase A, a downstream component of the cAMP signaling pathway, and enhanced by ligands that increased cAMP or directly activated protein kinase A. Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines. Thus, in contrast to mouse T cells, Amphiregulin synthesis by human T cells is regulated more by acute signals than pre-commitment of T cells to a particular cytokine pattern. This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses.

Show MeSH
Related in: MedlinePlus