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STAT3 governs hyporesponsiveness and granzyme B-dependent suppressive capacity in human CD4+ T cells.

ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) integrates key signals of cell surface immune receptors, yet its precise role in cluster of differentiation (CD)4(+) T cells is not well-established. Current research has indicated T-helper cell 17-inducing roles but also tolerogenic roles. To address this issue, human T cells were transduced with the constitutively active STAT3 mutant STAT3C. Following stimulation, STAT3C(+) T cells up-regulated IL-10 (4.1 ± 0.5-fold; P < 0.001) and granzyme B (2.5 ± 1.2, P < 0.05) secretion, combined with significantly reduced IFN-? (35 ± 5%), IL-2 (57 ± 4%), TNF-? (64 ± 8%), and IL-13 (89 ± 3%) secretion (P < 0.001). CD3/CD2- or CD3/CD28-activated STAT3C(+) T cells revealed reduced proliferation (53.4 ± 23.5% and 70.5 ± 10.4%, respectively), which was independent of IL-10 production and significantly suppressed effector T cell proliferation by 68.7 ± 10.6% and 65.9 ± 2.6%, respectively (P < 0.001). Phenotypically, STAT3C-transgenic CD4(+) T cells resembled effector T cells regarding expression of T regulatory cell markers, but up-regulated granzyme B expression levels by 2.4-fold (P < 0.05). Suppression was cell contact dependent and mediated by granzyme B-induced cell death, but was independent of IL-10 and TGF-?. Notably, peripheral blood CD4(+)CD45RA(-)lymphocyte activation gene-3(+)CD49(+) type 1 regulatory T cells revealed activation-induced hyperphosphorylation of STAT3. In agreement, pharmacological inhibition of STAT3 activation partially reverted hyporesponsiveness of peripheral type 1 regulatory T cells (increasing their division index from 0.46 ± 0.11 to 0.89 ± 0.04; P < 0.01). These observations indicate a clear-cut relation between activation of STAT3 and the acquisition of a tolerogenic program, which is also used by peripheral blood type 1 regulatory T cells.

SUBMITTER: Schmetterer KG

PROVIDER: S-EPMC4422363 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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STAT3 governs hyporesponsiveness and granzyme B-dependent suppressive capacity in human CD4+ T cells.

Schmetterer Klaus G KG Neunkirchner Alina A Wojta-Stremayr Daniela D Leitner Judith J Steinberger Peter P Pickl Winfried F WF

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20141114 3

Signal transducer and activator of transcription 3 (STAT3) integrates key signals of cell surface immune receptors, yet its precise role in cluster of differentiation (CD)4(+) T cells is not well-established. Current research has indicated T-helper cell 17-inducing roles but also tolerogenic roles. To address this issue, human T cells were transduced with the constitutively active STAT3 mutant STAT3C. Following stimulation, STAT3C(+) T cells up-regulated IL-10 (4.1 ± 0.5-fold; P < 0.001) and gra ...[more]

PMID: 25398767

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Project description:Endothelial cells (ECs) line the luminal surface of blood vessels and have an active role in the recruitment of leukocytes, including immune cell activation. Regulatory T cells (Tregs) are immune suppressor cells that maintain peripheral tolerance and must interact with the endothelium as they traffic into tissue. We hypothesized that human ECs could modulate Tregs and their suppressor function. Cocultures of CD4+ T cells with human umbilical vein ECs (HUVECs) or dermal microvascular ECs (HDMECs) were conducted and analyzed for activation and proliferation after 72 and 120?h using flow cytometry. In monocyte-depleted cultures, human ECs were found to support CD4+ T cell proliferation in the presence of external mitogens phytohemagglutinin or anti-CD3/28 antibodies (aCD3/28). Activation was shown by CD25 expression in these cells that also transiently expressed the Treg transcription factor FOXP3. HUVECs supported the specific concurrent proliferation of both effector T cells and Tregs when cocultured with aCD3/28. Purified Tregs were also functionally activated by prior coculture with EC to suppress effector T (Teff) cell proliferation. Both direct coculture and indirect coculture of EC and Treg showed activation of the Treg suppressive phenotype. However, whereas HUVEC showed enhancement of suppression by both mechanisms, HDMEC only supported Treg suppressive activity via the contact-independent mechanism. In the contact-independent cultures, the soluble mediators IL-6, GM-CSF, or G-CSF released from ECs following interferon-? activation were not responsible for the enhanced Treg suppressor function. Following direct coculture, Treg expression of inhibitory receptors PD-1 and OX40 was elevated while activated EC expressed the counter ligands programmed death ligand (PD-L)1 and PD-L2. Therefore, human ECs have a role in supporting T cell proliferation and increasing Treg suppressor function. This ability of EC to enhance Treg function could offer novel targets to boost Treg activity during inflammatory disorders.

Dataset Information

STAT3 governs hyporesponsiveness and granzyme B-dependent suppressive capacity in human CD4+ T cells.

Publications

STAT3 governs hyporesponsiveness and granzyme B-dependent suppressive capacity in human CD4+ T cells.

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