1. Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency.
- Author
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Rensing-Ehl A, Völkl S, Speckmann C, Lorenz MR, Ritter J, Janda A, Abinun M, Pircher H, Bengsch B, Thimme R, Fuchs I, Ammann S, Allgäuer A, Kentouche K, Cant A, Hambleton S, Bettoni da Cunha C, Huetker S, Kühnle I, Pekrun A, Seidel MG, Hummel M, Mackensen A, Schwarz K, and Ehl S
- Subjects
- Adolescent, Adult, Autoimmune Lymphoproliferative Syndrome genetics, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Cell Differentiation immunology, Child, Child, Preschool, Genetic Association Studies, Germ-Line Mutation, Humans, Immunologic Memory, Leukocyte Common Antigens metabolism, Loss of Heterozygosity, Receptors, Antigen, T-Cell, alpha-beta metabolism, T-Box Domain Proteins metabolism, T-Lymphocyte Subsets metabolism, Young Adult, T-bet Transcription Factor, 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, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets pathology, fas Receptor deficiency, fas Receptor genetics
- Abstract
Accumulation of CD3(+) T-cell receptor (TCR)αβ(+)CD4(-)CD8(-) double-negative T cells (DNT) is a hallmark of autoimmune lymphoproliferative syndrome (ALPS). DNT origin and differentiation pathways remain controversial. Here we show that human ALPS DNT have features of terminally differentiated effector memory T cells reexpressing CD45RA(+) (TEMRA), but are CD27(+)CD28(+)KLRG1(-) and do not express the transcription factor T-bet. This unique phenotype was also detected among CD4(+) or CD8(+) ALPS TEMRA cells. T-cell receptor β deep sequencing revealed a significant fraction of shared CDR3 sequences between ALPS DNT and both CD4(+) and CD8(+)TEMRA cells. Moreover, in ALPS patients with a germ line FAS mutation and somatic loss of heterozygosity, in whom biallelic mutant cells can be tracked by absent Fas expression, Fas-negative T cells accumulated not only among DNT, but also among CD4(+) and CD8(+)TEMRA cells. These data indicate that in human Fas deficiency DNT cannot only derive from CD8(+), but also from CD4(+) T cells. Furthermore, defective Fas signaling leads to aberrant transcriptional programs and differentiation of subsets of CD4(+) and CD8(+) T cells. Accumulation of these cells before their double-negative state appears to be an important early event in the pathogenesis of lymphoproliferation in ALPS patients., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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