T cell receptors in an IL-10-secreting amino acid copolymer-specific regulatory T cell line that mediates bystander immunosuppression

Zhang, Hong; Stern, Joel N. H.; Strominger, Jack L.

doi:10.1073/pnas.0813197106

Cited by 8 publications

(8 citation statements)

References 40 publications

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“…Tolerogenic DCs produced IL-10 [21,72,73] and autocrine activation of the IL-10 receptor (IL-10R) signaling helped to maintain DCs in an immature tolerogenic state [50,74]. IL-10 expressing DCs were shown to generate Tregs and Tr1 cells, which were also IL-10 producing cells [75-78]. Furthermore, IL-10 contributed to sustained expression of Foxp3 [46,79], TGFβ-Receptor-2 [80] and TGFβ [81,82] by recently activated Tregs, thus stabilizing Treg phenotype and functions[67,81].…”

Section: Text Of Reviewmentioning

confidence: 99%

Current status of interleukin-10 and regulatory T-cells in cancer

Dennis¹,

Blatner²,

Gounari³

et al. 2013

Current Opinion in Oncology

234

175

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Purpose of review Tumor growth elicits antigen-specific cytotoxic as well as immune suppressive responses. Interleukin-10 (IL-10) is a key immune-suppressive cytokine produced by regulatory T-cells (Tregs) and by helper T-cells (TH). Here we review pleiotropic functions of IL-10 that impact the immune pathology of cancer. Recent findings The role of IL-10 in cancer has become less certain with knowledge of its immune stimulatory functions. IL-10 is needed for T-helper cell functions, T-cell immune surveillance, and suppression of cancer-associated inflammation. By promoting tumor specific immune surveillance and hindering pathogenic inflammation IL-10 is emerging as a key cytokine in the battle of the host against cancer. Summary IL-10 functions at the cross roads of immune stimulation and immune suppression in cancer. Immunological mechanisms of action of IL-10 can be ultimately exploited to develop novel and effective cancer therapies.

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Section: Text Of Reviewmentioning

confidence: 99%

Current status of interleukin-10 and regulatory T-cells in cancer

Dennis¹,

Blatner²,

Gounari³

et al. 2013

Current Opinion in Oncology

234

175

View full text Add to dashboard Cite

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“…Such TCR inherent properties, including but not limited to avidity and affinity for cognate antigen, to direct T-helper subset differentiation have been reported for murine CD4 T regulatory (Tregs) cells, IL-10 secreting cells and Th17 cells [60–63]. In a similar vein, it was shown that TCRs cloned from human and Rhesus macaque viral suppressive CD8 T cells and expressed in species-homologous naïve CD8 T cells rendered those cells suppressive as well.…”

Section: Discussionmentioning

confidence: 66%

Avidity of human T cell receptor engineered CD4+ T cells drives T-helper differentiation fate

Adair

Kim

Pratt

et al. 2016

Cellular Immunology

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The role of the T cell receptor (TCR) in antigen recognition and activation of T lymphocytes is well established. However, how the TCR affects T-helper differentiation/skewing is less well understood, particularly for human CD4+ (CD4) T cell subsets. Here we investigate the role of TCR specific antigen avidity in differentiation and maintenance of human Th1, Th2 and Th17 subsets. Two human TCRs, both specific for the same peptide antigen but with different avidities, were cloned and expressed in human CD4 T cells. These TCR engineered cells were then stimulated with specific antigen in unskewed and T-helper skewed conditions. We show that TCR avidity can control the percentage of IL-4 and IFN-γ co-expression in unskewed TCR engineered cells, that effector function can be maintained in a TCR avidity-dependent manner in skewed TCR engineered cells, and that increased TCR avidity can accelerate Th1 skewing of TCR engineered cells.

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“…Retrovirus Transduction. Vector control or YFAK-specific TCRαβ retrovirus was generated, as described (2,6). Bone marrow was isolated from donor SJL/J mice and purified for lineage negative cells by MACS (Miltenyi Biotec) according to manufacturer's protocol and grown for 2 d in tissue culture with recombinant IL-3, IL-6, and SCF.…”

Section: Methodsmentioning

confidence: 99%

“…multiple sclerosis | immunosuppression | retrovirus | cytokines T he random amino acid copolymers poly(Y,F,A,K) n (called YFAK), and poly(Y,E,A,K)n [YEAK, Copaxone, a drug widely used to treat multiple sclerosis (MS)] induce the differentiation of regulatory T cells that secrete IL-10 (1). This cytokine mediates bystander immunosuppression and leads to amelioration of experimental autoimmune encephalomyelitis (EAE), the murine model of the human disease MS. YFAKspecific T cell lines have been generated from SJL mice treated with YFAK, and the nature of their T cell receptors has been investigated (2). Interestingly, these regulatory T cells preferentially used Vα3.2Vβ14, and, to only a slightly lesser extent, Vβ4 with more variable Vα segments.…”

mentioning

confidence: 99%

Genetically modified hematopoietic stem/progenitor cells that produce IL-10–secreting regulatory T cells

Ng¹,

Leno-Durán²,

Samanta³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Random amino acid copolymers used in the treatment of multiple sclerosis in man or experimental autoimmune encephalomyelitis (EAE) in mice [poly(Y,E,A,K)n, known as Copaxone, and poly(Y,F,A,K)n] function at least in part by generation of IL-10–secreting regulatory T cells that mediate bystander immunosuppression. The mechanism through which these copolymers induce Tregs is unknown. To investigate this question, four previously described Vα3.2 Vβ14 T cell receptor (TCR) cDNAs, the dominant clonotype generated in splenocytes after immunization of SJL mice, that differed only in their CDR3 sequences were utilized to generate retrogenic mice. The high-level production of IL-10 as well as IL-5 and small amounts of the related cytokines IL-4 and IL-13 by CD4+ T cells isolated from the splenocytes of these mice strongly suggests that the TCR itself encodes information for specific cytokine secretion. The proliferation and production of IL-10 by these Tregs was costimulated by activation of glucocorticoid-induced TNF receptor (GITR) (expressed at high levels by these cells) through its ligand GITRL. A mechanism for generation of cells with this specificity is proposed. Moreover, retrogenic mice expressing these Tregs were protected from induction of EAE by the appropriate autoantigen.

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T cell receptors in an IL-10-secreting amino acid copolymer-specific regulatory T cell line that mediates bystander immunosuppression

Cited by 8 publications

References 40 publications

Current status of interleukin-10 and regulatory T-cells in cancer

Current status of interleukin-10 and regulatory T-cells in cancer

Avidity of human T cell receptor engineered CD4+ T cells drives T-helper differentiation fate

Genetically modified hematopoietic stem/progenitor cells that produce IL-10–secreting regulatory T cells

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