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SHR Neuro Cancer Cardio Lipid Metab Microb

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; Ehl, S.
Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency.
Blood. 2014; 124(6):851-860 Doi: 10.1182/blood-2014-03-564286 [OPEN ACCESS]
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Co-authors Med Uni Graz: Seidel Markus
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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.
Find related publications in this database (using NLM MeSH Indexing): Adolescent -; Adult -; Autoimmune Lymphoproliferative Syndrome - genetics; Autoimmune Lymphoproliferative Syndrome - immunology; Autoimmune Lymphoproliferative Syndrome - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; 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 - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; Young Adult -; fas Receptor - deficiency; fas Receptor - genetics