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-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 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.

• Authors: Anne Rensing-Ehl, Simon Völkl, Carsten Speckmann, Myriam Ricarda Lorenz, Julia Ritter, Ales Janda, Mario Abinun, Hanspeter Pircher, Bertram Bengsch, Robert Thimme, Ilka Fuchs, Sandra Ammann, Andrea Allgäuer, Karim Kentouche, Andrew Cant, Sophie Hambleton, Claudia Bettoni da Cunha, Sebastian Huetker, Ingrid Kühnle, Arnulf Pekrun, Markus G Seidel, Michael Hummel, Andreas Mackensen, Klaus Schwarz, Stephan Ehl
• Journal: Blood (Blood) Vol. 124 Issue 6 Pg. 851-60 (Aug 07 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24894771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• FAS protein, human
• Receptors, Antigen, T-Cell, alpha-beta
• T-Box Domain Proteins
• T-box transcription factor TBX21
• fas Receptor
• Leukocyte Common Antigens

Topics

• Adolescent
• Adult
• Autoimmune Lymphoproliferative Syndrome (genetics, immunology, pathology)
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• CD8-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Cell Differentiation (genetics, immunology)
• Child
• Child, Preschool
• Genetic Association Studies
• Germ-Line Mutation
• Humans
• Immunologic Memory
• Leukocyte Common Antigens (metabolism)
• Loss of Heterozygosity
• Receptors, Antigen, T-Cell, alpha-beta (metabolism)
• T-Box Domain Proteins (metabolism)
• T-Lymphocyte Subsets (immunology, metabolism, pathology)
• Young Adult
• fas Receptor (deficiency, genetics)