The role of interleukin-6 in mitogenic T-cell activation: Detection of interleukin-2 heteronuclear RNA by polymerase chain reaction

Abstract Background Intestinal macrophages are key immune cells in the maintenance of intestinal immune homeostasis and have a role in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms by which macrophages exert a pathological influence in both ulcerative colitis (UC) and Crohn disease (CD) are not yet well understood. Methods We purified intestinal macrophages from gastrointestinal mucosal biopsies (patients with UC, patients with CD, and healthy donors) and analyzed their transcriptome by RNA sequencing and bioinformatics, confirming results with quantitative polymerase chain reaction and immunohistochemistry. Results Compared with those of healthy donors, intestinal macrophages in patients with UC and with CD showed cellular reprograming of 1287 and 840 dysregulated genes, respectively (false discovery rate ≤ 0.1). The UC and CD intestinal macrophages showed an activated M1 inflammatory phenotype and the downregulation of genes engaged in drug/xenobiotic metabolism. Only macrophages from CD showed, concomitant to an M1 phenotype, a significant enrichment in the expression of M2 and fibrotic and granuloma-related genes. For the first time, we showed (and validated by quantitative polymerase chain reaction and immunohistochemistry) that intestinal macrophages in patients with IBD present both M1 and M2 features, as recently described for tumor-associated macrophages, that affect key pathways for IBD pathology, represented by key markers such as MMP12 (fibrosis), CXCL9 (T-cell attraction), and CD40 (T-cell activation). Conclusions Our data support the therapeutic targeting of macrophages to maintain remission in IBD but also indicate that a shift toward an M2 program—as proposed by some reports—may not limit the recruitment and activation of T cells because M2 features do not preclude M1 activation in patients with UC or CD and could exacerbate M2-related CD-specific features such as fibrosis and the formation of granulomas.

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An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽

10.1182/blood-2009-06-225987 ◽

2010 ◽

Vol 115 (2) ◽

pp. 265-273 ◽

Cited By ~ 212

Author(s):

Graziella Curtale ◽

Franca Citarella ◽

Claudia Carissimi ◽

Marina Goldoni ◽

Nicoletta Carucci ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Death ◽

T Cell ◽

T Lymphocytes ◽

T Cell Activation ◽

Cell Activation ◽

Interleukin 2 ◽

Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

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The role of accessory cells in polyclonal T cell activation. I. Both induction of interleukin 2 production and of interleukin 2 responsiveness by concanavalin A are accessory cell dependent

European Journal of Immunology ◽

10.1002/eji.1830130103 ◽

1983 ◽

Vol 13 (1) ◽

pp. 1-6 ◽

Cited By ~ 59

Author(s):

Thomas Hünig ◽

Michael Loos ◽

Anneliese Schimpl

Keyword(s):

T Cell ◽

T Cell Activation ◽

Concanavalin A ◽

Cell Activation ◽

Interleukin 2 ◽

Accessory Cell ◽

Accessory Cells

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Accessory cell-derived helper signals in human T-cell activation with phytohemagglutinin: Induction of interleukin 2, responsiveness of interleukin 6, and production of interleukin 2 by interleukin 1

Cytokine ◽

10.1016/1043-4666(90)90042-r ◽

1990 ◽

Vol 2 (1) ◽

pp. 45-54 ◽

Cited By ~ 10

Author(s):

R Kuhweide

Keyword(s):

T Cell ◽

T Cell Activation ◽

Interleukin 6 ◽

Cell Activation ◽

Interleukin 1 ◽

Interleukin 2 ◽

Accessory Cell ◽

Human T Cell

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Anti-Thy-1-mediated T cell activation. Role of soluble factors and expression of interleukin 2 receptors on T cells

European Journal of Immunology ◽

10.1002/eji.1830110602 ◽

1981 ◽

Vol 11 (6) ◽

pp. 445-450 ◽

Cited By ~ 30

Author(s):

Yoshiteru Konaka ◽

Michael A. Norcross ◽

Vernon C. Maino ◽

Richard T. Smith

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Interleukin 2 ◽

Soluble Factors

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Cowpox virus encodes a protein that binds B7.1 and B7.2 and subverts T cell costimulation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909414116 ◽

2019 ◽

Vol 116 (42) ◽

pp. 21113-21119 ◽

Cited By ~ 1

Author(s):

Xiaoli Wang ◽

Sytse J. Piersma ◽

Jabari I. Elliott ◽

John M. Errico ◽

Maria D. Gainey ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Interleukin 2 ◽

Cowpox Virus ◽

Cell Responses ◽

Cd28 Costimulation ◽

Infected Cells ◽

Culture Supernatants

Costimulation is required for optimal T cell activation, yet it is unclear whether poxviruses dedicatedly subvert costimulation during infection. Here, we report that the secreted M2 protein encoded by cowpox virus (CPXV) specifically interacts with human and murine B7.1 (CD80) and B7.2 (CD86). We also show that M2 competes with CD28 and CTLA4 for binding to cell surface B7 ligands, with stronger efficacy against CD28. Functionally, recombinant M2 and culture supernatants from wild-type (WT) but not M2-deficient (∆M2) CPXV-infected cells can potently suppress B7 ligand-mediated T cell proliferation and interleukin-2 (IL-2) production. Furthermore, we observed increased antiviral CD4 and CD8 T cell responses in C57BL/6 mice challenged by ∆M2 CPXV compared with WT virus. These differences in immune responses to ∆M2 and WT CPXV were not observed in CD28-deficient mice. Taken together, our findings define a mechanism of viral sabotage of T cell activation that highlights the role of CD28 costimulation in host defense against poxvirus infections.

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