IL-10 and TGF-  induce alloreactive CD4+CD25- T cells to acquire regulatory cell function

Chen, Zong Ming; O’Shaughnessy, Matthew J.; Gramaglia, Irene; Panoskaltsis‐Mortari, Angela; Murphy, William J.; Narula, Satwant K.; Roncarolo, Maria Grazia; Blazar, Bruce R.

doi:10.1182/blood-2002-09-2798

Cited by 161 publications

(119 citation statements)

References 36 publications

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“…Although prior studies show that CD4 þ CD25 À T cells can be induced into suppressing CD4 þ CD25 þ T cells by peripheral expansion, 36 we were able to demonstrate that the increase in Treg frequency was derived from natural Treg selfexpansion promoted by factors secreted by Huh7 cells and not from conversion of naïve CD4 þ CD25 À T cells. Our data also show that Huh7 supernatants and not normal hepatocyte culture supernatants inhibited PBMC proliferation in dose-dependent manner.…”

Section: Discussionmentioning

confidence: 58%

Hepatocellular carcinoma cell supernatants increase expansion and function of CD4+CD25+ regulatory T cells

Cao

Cabrera

et al. 2007

Laboratory Investigation

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Dysfunction of the host immune system in cancer patients can be due to a number of factors, including suppression of tumor-associated antigen reactive lymphocytes by CD4 þ CD25 þ regulatory T (Treg) cells. Several studies suggest that Tregs are elevated in cancer patients and that depletion of Tregs may enhance the antitumor immunity of host, but the pathogenic and mechanistic relationship between cancer and Tregs is still unclear. In this report, we show that Tregs are increased in peripheral blood mononuclear cells (PBMCs) from hepatocellular carcinoma (HCC) patients and positively correlate with tumor burden. When PBMCs are co-cultured with human hepatoma cell lines Huh7, HepG2, and Hclone5, CD4 þ CD25 þ -T cell populations increase in frequency and undergo phenotypic and functional changes. CD45RA, CD45RO, CD69, CD62L, GITR, CTLA-4, Ki67, granzyme A, granzyme B, and FOXP3 expression were upregulated in CD4 þ CD25 þ cells after in vitro exposure to HCC cell lines. CD4 þ CD25 þ T cells from PBMCs that were co-cultured with Huh7 cells also have higher suppressor ability compared to that of the CD4 þ CD25 þ T cells from control PBMC. Huh7 culture supernatants appear to promote CD4 þ CD25 þ T-cell proliferation and inhibit CD4 þ CD25 À T-cell proliferation. In conclusion, these results strongly suggest that tumor-related factors not only induce and expand CD4 þ CD25 þ cells, but also enhance their suppressor ability.

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Section: Discussionmentioning

confidence: 58%

Hepatocellular carcinoma cell supernatants increase expansion and function of CD4+CD25+ regulatory T cells

Cao

Cabrera

et al. 2007

Laboratory Investigation

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“…Decorin, a gene product known for its potent binding capacity for transforming growth factor-h (37 -39), migration inhibitory factor (40 -43), and interleukin-1 receptor antagonist (44,45), is increased in expression in T regs from patients with glioblastoma multiforme, consistent with the premise of active inhibition of immune responses by this population of cells (15). The substantial up-regulation of decorin (up to 33-fold) may be of central importance in understanding the role of transforming growth factor-h in T reg induction and activity in these patients (46,47). Furthermore, it is interesting to note that, although not statistically significant by ANOVA, the interleukin-2 receptor was expressed at higher levels in the CD4 + and CD8 + cells of healthy volunteers compared with glioblastoma multiforme patients, whereas this receptor was expressed at lower levels in T regs from healthy volunteers compared with glioblastoma multiforme patients.…”

Section: Discussionmentioning

confidence: 85%

Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T Cells in Patients with Malignant Glioma Reveals Differential Expression of the Immunologic Transcriptome Compared with T Cells from Healthy Volunteers

Learn¹,

Fecci²,

Schmittling³

et al. 2006

Clinical Cancer Research

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Purpose: Analyses of T-cell mRNA expression profiles in glioblastoma multiforme has not been previously reported but may help to define and characterize the immunosuppressed phenotype in patients with this type of cancer. Experimental Design: We did microarray studies that have shown significant and fundamental differences in the expression profiles of CD4 + and CD8 + T cells and immunosuppressive CD4 + CD25 + CD45RO + FoxP3 + regulatory T cells (T reg ) from normal healthy volunteers compared with patients with newly diagnosed glioblastoma multiforme. For these investigations, we isolated total RNA from enriched CD4 + and CD8 + Tcell or T reg cell populations from age-matched individuals and did microarray analyses. Results: ANOVA and principal components analysis show that the various T cell compartments exhibit consistently similar mRNA expression profiles among individuals within either healthy or brain tumor groups but reflect significant differences between these groups. Compared with healthy volunteers, CD4 + and CD8 + T cells from patients with glioblastoma multiforme display coordinate down-regulation of genes involved in T cell receptor ligation, activation, and intracellular signaling. In contrast,T regs from patients with glioblastoma multiforme exhibit increased levels of transcripts involved in inhibiting host immunity. Conclusion: Our findings support the notion that key differences between expression profiles in T-cell populations from patients with glioblastoma multiforme results from differential expression of the immunologic transcriptome, such that a limited number of genes are principally important in producing the dysregulated T-cell phenotype.

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“…Using ELISA to detect the spontaneously released IL-10, they noted that high IL-10 production correlated with a low incidence of GVHD. Chen et al 17 reported the induction of alloantigen-specific tolerance and generation of regulatory cells by pretreatment with IL-10/TGF-b. This study also identifies IL-10-producing cells that respond to allostimulation.…”

Section: Discussionmentioning

confidence: 99%

Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD

Weston

Geczy

Briscoe

2005

Bone Marrow Transplant

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IL-10 and TGF- induce alloreactive CD4+CD25- T cells to acquire regulatory cell function

Cited by 161 publications

References 36 publications

Hepatocellular carcinoma cell supernatants increase expansion and function of CD4+CD25+ regulatory T cells

Hepatocellular carcinoma cell supernatants increase expansion and function of CD4+CD25+ regulatory T cells

Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T Cells in Patients with Malignant Glioma Reveals Differential Expression of the Immunologic Transcriptome Compared with T Cells from Healthy Volunteers

Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD

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