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

Sze Ling Ng, Ester Leno-Duran, Dibyendu Samanta, Steven C. Almo, Jack L. Strominger

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2634-2639
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number7
DOIs
StatePublished - Feb 12 2019

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Regulatory T-Lymphocytes
Hematopoietic Stem Cells
Autoimmune Experimental Encephalomyelitis
T-Cell Antigen Receptor
Interleukin-10
Cytokines
Interleukin-13
Tumor Necrosis Factor Receptors
Interleukin-5
Autoantigens
Interleukin-4
Immunosuppression
Glucocorticoids
Multiple Sclerosis
Immunization
Complementary DNA
Ligands
T-Lymphocytes
Amino Acids

Keywords

  • Cytokines
  • Immunosuppression
  • Multiple sclerosis
  • Retrovirus

ASJC Scopus subject areas

  • General

Cite this

Genetically modified hematopoietic stem/progenitor cells that produce IL-10–secreting regulatory T cells. / Ng, Sze Ling; Leno-Duran, Ester; Samanta, Dibyendu; Almo, Steven C.; Strominger, Jack L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 7, 12.02.2019, p. 2634-2639.

Research output: Contribution to journalArticle

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