- Title
- Expansion of somatically reverted memory CD8(+) T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus
- Creator
- Palendira, Umaimainthan; Low, Carol; Giliani, Silvia; Buckley, Rebecca H.; Grimbacher, Bodo; Alvaro, Frank; Klion, Amy D.; Nichols, Kim E.; Adelstein, Stephen; Rickinson, Alan B.; Tangye, Stuart G.; Bell, Andrew I; Ma, Cindy S.; Abbott, Rachel J. M.; Phan, Tri Giang; Riminton, D. Sean; Choo, Sharon; Smart, Joanne M.; Lougaris, Vassilios
- Relation
- Journal of Experimental Medicine Vol. 209, Issue 5, p. 911-922
- Publisher Link
- http://dx.doi.org/10.1084/jem.20112391
- Publisher
- Rockefeller University Press
- Resource Type
- journal article
- Date
- 2012
- Description
- 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. X-linked lymphoproliferative disease (XLP-1; referred to hereafter as XLP) is a primary immunodeficiency (PID) resulting from loss of function mutations in SH2D1A (Coffey et al., 1998; Nichols et al., 1998; Sayos et al., 1998). SH2D1A encodes SLAM-associated protein (SAP), a cytoplasmic adaptor protein involved in intracellular signaling downstream of the SLAM family of surface receptors (Ma et al., 2007; Schwartzberg et al., 2009; Cannons et al., 2011). XLP patients exhibit exquisite sensitivity to infection with the herpes group virus EBV (Bar et al., 1974; Purtilo et al., 1975; Sumegi et al., 2000; Nichols et al., 2005b). In contrast to healthy individuals, in whom primary infection is often asymptomatic (Hislop et al., 2007), many XLP patients suffer from severe, and often-fatal, fulminant infectious mononucleosis caused by an inability to control EBV infection (Nichols et al., 2005b; Ma et al., 2007). XLP patients can also develop hypogammaglobulinemia and B-lymphoma (Sumegi et al., 2000; Nichols et al., 2005b; Ma et al., 2007). Several immune cell defects have been identified in XLP patients and Sh2d1a-deficient mice. These include reduced cytotoxicity of CD8+ T and NK cells, abolished NKT cell development, and impaired humoral immunity caused by compromised function of SAP-deficient CD4+ T cells (Nichols et al., 2005b; Ma et al., 2007; Schwartzberg et al., 2009; Cannons et al., 2011). We recently showed that SAP-deficient CD8+ T cells selectively fail to respond to B cell targets, yet they can be activated normally by other APCs, such as monocytes, DCs, or fibroblasts (Hislop et al., 2010; Palendira et al., 2011). Because EBV persists predominantly in B cells (Hislop et al., 2007), this provides a mechanism for the molecular pathogenesis of EBV infection in XLP. However, variability in the clinical presentation of XLP and the lack of a genotype-phenotype correlation (Sumegi et al., 2000; Booth et al., 2011) suggest that other factors influence disease progression, pathogenesis, and severity. Indeed, despite the presence of persistently high EBV viral loads (Chaganti et al., 2008), some XLP patients have milder clinical features, such as isolated hypogammaglobulinemia, and some exceed the mean life expectancy of XLP by several decades (Sumegi et al., 2000; Booth et al., 2011). Milder clinical presentations in PIDs are often associated with somatic reversion, which results from a spontaneous genetic change in a disease-causing mutation in a somatic cell (Hirschhorn, 2003; Wada and Candotti, 2008). Cells harboring somatic reversions often expand because of a growth advantage or selective pressure (Hirschhorn, 2003; Wada and Candotti, 2008). Revertant somatic mosaicisms have been reported in several PIDs, including SCID (caused by mutations in ADA [Hirschhorn et al., 1996], IL2RG [Stephan et al., 1996; Speckmann et al., 2008], RAG1 [Wada et al., 2005], and CD3ζ [Rieux-Laucat et al., 2006]), X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID; Nishikomori et al., 2004), Wiskott-Aldrich syndrome (WAS; Ariga et al., 2001; Wada et al., 2003; Stewart et al., 2007; Trifari et al., 2010), and lymphocyte adhesion deficiency-1 (LAD-1; Tone et al., 2007; Uzel et al., 2008). Although somatic reversion is infrequent overall, it has been observed in 11%, 18%, and 35% of patients with WAS (Stewart et al., 2007), Fanconi anemia (Kalb et al., 2007), and epidermolysis bullosa (Jonkman and Pasmooij, 2009), respectively. The resulting phenotype of patients with somatic reversion/mosaicism can range from mild immune defects to a completely normal state (Hirschhorn, 2003; Wada and Candotti, 2008). In this study, we examined reversion in XLP patients who have not undergone BM transplant and present evidence demonstrating that somatic mosaicism exists in a high proportion of patients. Somatic reversion was restricted to CD8+ T cells and correlated with exposure to EBV. Thus, the extrinsic selective effect of the virus appeared to be responsible for expanding the reverted SAP+ cells. Moreover, these SAP+ CD8+ T cells displayed EBV-specific cytotoxicity, indicating that they have the potential to protect XLP patients from the severe effects of EBV infection and possible progression to lymphoma in these individuals.
- Subject
- memory CD8+ T cells; X-linked lymphoproliferative disease; Epstein-Barr virus; immunodeficiency
- Identifier
- http://hdl.handle.net/1959.13/1318622
- Identifier
- uon:23657
- Identifier
- ISSN:0022-1007
- Language
- eng
- Full Text
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