Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency

Rensing-Ehl A, Voelkl 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, Da Cunha CB, Huetker S, Kuehnle I, Pekrun A, Seidel MG, Hummel M, Mackensen A, Schwarz K, Ehl S (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Blood American Society of Hematology

Publisher: American Society of Hematology

Book Volume: 124

Pages Range: 851-60

Journal Issue: 6

DOI: 10.1182/blood-2014-03-564286

Abstract

Accumulation of CD3(+) T-cell receptor (TCR)??(+)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 ? 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.

Authors with CRIS profile

Andrea Allgäuer Department of Medicine 5 – Haematology and Oncology Andreas Mackensen Lehrstuhl für Innere Medizin V

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universitätsklinikum Göttingen DE Germany (DE) Klinikverbund Bremen (Gesundheit Nord) DE Germany (DE) Medizinische Universität Graz AT Austria (AT) Charité - Universitätsmedizin Berlin DE Germany (DE) Universitätsklinikum Freiburg DE Germany (DE) Universität Ulm DE Germany (DE) Great North Children's Hospital GB United Kingdom (GB) Universitätsklinikum Jena DE Germany (DE)

How to cite

APA:

Rensing-Ehl, A., Voelkl, S., Speckmann, C., Lorenz, M.R., Ritter, J., Janda, A.,... Ehl, S. (2014). Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency. Blood, 124(6), 851-60. https://doi.org/10.1182/blood-2014-03-564286

MLA:

Rensing-Ehl, Anne, et al. "Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency." Blood 124.6 (2014): 851-60.

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