title: Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus.
abstract: Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8(+) T cell subset, displayed a CD45RA(-)CCR7(-) effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8(+) SAP(+) T cells, but not SAP(-) cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia. m.palendira@garvan.org.au
authors.forename: Umaimainthan
authors.initials: U
authors.lastname: Palendira
authors.forename: Carol
authors.initials: C
authors.lastname: Low
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Bell
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Rachel J M
authors.initials: RJ
authors.lastname: Abbott
authors.forename: Tri Giang
authors.initials: TG
authors.lastname: Phan
authors.forename: D Sean
authors.initials: DS
authors.lastname: Riminton
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smart
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Buckley
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Frank
authors.initials: F
authors.lastname: Alvaro
authors.forename: Amy D
authors.initials: AD
authors.lastname: Klion
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.forename: Stephen
authors.initials: S
authors.lastname: Adelstein
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D004854:Herpesvirus 4, Human; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D019562:Viral Load
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein