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

作者：Rensing Ehl Anne; Voelkl Simon; Speckmann Carsten; Lorenz Myriam Ricarda; Ritter Julia; Janda Ales; Abinun Mario; Pircher Hanspeter; Bengsch Bertram; Thimme Robert; Fuchs Ilka; Ammann Sandra; Allgaeuer Andrea; Kentouche Karim; Cant Andrew; Hambleton Sophie; da Cunha Claudia Bettoni; Huetker Sebastian; Kuehnle Ingrid; Pekrun Arnulf; Seidel Markus G; Hummel Michael; Mackensen Andreas; Schwarz Klaus; Ehl Stephan^*

来源：Blood, 2014, 124(6): 851-860.

DOI：10.1182/blood-2014-03-564286

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.

• 出版日期2014-8-7