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

Abstract

Accumulation of CD3+T-cell receptor (TCR)αβ +CD4-CD8-double-negativeTcells (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.