The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome.
Patients with X-linked lymphoproliferative syndrome (XLP) experience excessive T cell proliferation after primary Epstein-Barr virus (EBV) infection, due to mutations in the signalling lymphocyte activation molecule (SLAM) associated protein (SAP) molecule. We examined the impact of dysfunctional proliferative control on the extent of CD8+ T cell differentiation in XLP patients who recovered from primary EBV infection. Although these young patients have normal numbers of lytic and latent EBV-epitope-specific CD8+ T cells, they were extremely differentiated as defined by loss of CCR7 and CD27, low telomerase activity and very short telomeres. This was not a direct effect arising from the loss of SAP, but was due to excessive T cell stimulation due to this defect. Thus, transduction of XLP CD8+ T cells with the catalytic component of telomerase (hTERT), but not SAP, prevented telomere loss and considerably extended proliferative lifespan in vitro. These results indicate that excessive proliferation in CD8+ T cells in XLP patients may lead to end-stage differentiation and loss of functional EBV-specific CD8+ T cells through replicative senescence. This may contribute to the defective immunity found in XLP patients who survive acute EBV infection who develop EBV-related B cell lymphomas before the fourth decade of life.
Department of Immunology and Molecular Pathology, Royal Free and University College Medical School, London, UK.
Fiona J
FJ
Plunkett
Ornella
O
Franzese
Lavina L
LL
Belaramani
Jean M
JM
Fletcher
Kimberly C
KC
Gilmour
Reza
R
Sharifi
Naeem
N
Khan
Andrew D
AD
Hislop
Andrea
A
Cara
Mike
M
Salmon
H Bobby
HB
Gaspar
Malcom H A
MH
Rustin
David
D
Webster
Arne N
AN
Akbar
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D016086:Lentivirus / Q000235:genetics; D008136:Longevity; D016393:Lymphoma, B-Cell / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D019098:Telomerase / Q000737:chemistry; D016615:Telomere / Q000737:chemistry / Q000648:ultrastructure*; D013997:Time Factors
D004268:DNA-Binding Proteins; D000939:Epitopes; D049452:Green Fluorescent Proteins; D019098:Telomerase