Abinun M

Allgauer A

Ammann S

Bengsch B

Cant A

da Cunha CB

Ehl S

Fuchs I

Hambleton S

Huetker S

Hummel M

Janda A

Kentouche K

Kuhnle I

Lorenz MR

Mackensen A

Pekrun A

Pircher H

Rensing-Ehl A

Ritter J

Schwarz K

Seidel MG

Speckmann C

Thimme R

Volkl S

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

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

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

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