期刊
BLOOD
卷 124, 期 6, 页码 851-860出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-03-564286
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资金
- German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung) [1 EO 0803, 01GM1111B]
- Interdisciplinary Center for Clinical Research Erlangen (Interdisziplinares Zentrum fur Klinische Forschung project) [A58]
- The Sir Jules Thorn Charitable Trust [12JTA] Funding Source: researchfish
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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