Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome

Blood. 2016 Jul 14;128(2):227-38. doi: 10.1182/blood-2015-11-685024. Epub 2016 Apr 20.

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Autoimmune Lymphoproliferative Syndrome / immunology*
  • Autoimmune Lymphoproliferative Syndrome / pathology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Differentiation / immunology*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Lectins, C-Type / immunology
  • Leukocyte Common Antigens / immunology
  • Male
  • Proto-Oncogene Proteins c-akt / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Immunologic
  • Signal Transduction / immunology*
  • TOR Serine-Threonine Kinases / immunology*
  • Trans-Activators / immunology

Substances

  • KLRG1 protein, human
  • Lectins, C-Type
  • Receptors, Antigen, T-Cell
  • Receptors, Immunologic
  • Trans-Activators
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Leukocyte Common Antigens