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

Lookup NU author(s): Dr Mario Abinun, Professor Andrew Cant, Professor Sophie HambletonORCiD


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

Publication metadata

Author(s): Rensing-Ehl A, Volkl S, Speckmann C, Lorenz MR, Ritter J, Janda A, Abinun M, Pircher H, Bengsch B, Thimme R, Fuchs I, Ammann S, Allgauer A, Kentouche K, Cant A, Hambleton S, da Cunha CB, Huetker S, Kuhnle I, Pekrun A, Seidel MG, Hummel M, Mackensen A, Schwarz K, Ehl S

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2014

Volume: 124

Issue: 6

Pages: 851-860

Print publication date: 07/08/2014

Online publication date: 03/06/2014

Acceptance date: 27/05/2014

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology


DOI: 10.1182/blood-2014-03-564286


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Funder referenceFunder name
01GM1111BGerman Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung)
1 EO 0803German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung)
A58Interdisciplinary Center for Clinical Research Erlangen (Interdisziplinares Zentrum fur Klinische Forschung project)