4.6 Article

Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGFβ-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis

Journal

JOURNAL OF IMMUNOLOGY
Volume 180, Issue 11, Pages 7327-7337

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.180.11.7327

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Funding

  1. NIAID NIH HHS [AI435801, R01 AI043458-09, R01 AI043458-10, R01 AI043458] Funding Source: Medline
  2. NINDS NIH HHS [P01 NS038037, P01 NS038037-07, NS38037] Funding Source: Medline

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CD4(+)CD25(+) regulatory T cells (Tregs) are essential for maintaining self-tolerance and immune homeostasis. Here we characterize a novel subset of CD4+CD25+ Tregs that express latency-associated peptide (LAP) on their cell surface (CD4(+)CD25(+)LAP(+) cells). CD4(+)CD25(+)LAP(+) cells express elevated levels of Foxp3 and Treg-associated molecules (CTLA4, glucocorticoid-induced TNFR-related gene), secrete TGF beta, and express both cell surface TGF beta and surface receptors for TGF beta. In vitro, the suppressive function of CD4(+)CD25(+)LAP(+) cells is both cell contact and soluble factor dependent; this contrasts with CD4(+)CD25(+)LAP(-) cells, which are mainly cell contact dependent. In a model of experimental autoimmune encephalomyelitis, CD4(+)CD25(+)LAP(+) cells exhibit more potent suppressive activity than CD4(+)CD25(+)LAP(-) cells, and the suppression is TGF beta dependent. We further show that CD4(+)CD25(+)LAP(+) cells suppress myelin oligodendrocyte glycoprotein-specific immune responses by inducing Foxp3 and by inhibiting IL-17 production. Our findings demonstrate that CD4(+)CD25(+) Tregs are a heterogeneous population and that the CD4(+)CD25(+) subset that expresses LAP functions in a TGF beta-dependent manner and has greater in vivo suppressive properties. Our work helps elucidate the ambiguity concerning the role of TGF beta in CD4(+)CD25(+) Treg-mediated suppression and indicates that LAP is an authentic marker able to identify a TGF beta-expressing CD4(+)CD25(+) Treg subset.

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