Submitted April 24, 2006
Accepted June 9, 2006
Hypogammaglobulinemia and exacerbated CD8 T cell
mediated immunopathology in SAP-deficient mice with
chronic LCMV infection mimics human XLP disease
Shane Crotty*, Megan M. McCausland, Rachael D. Aubert, E. John Wherry, and Rafi Ahmed
Division of Vaccine Discovery,La Jolla Institute for Allergy and Immunology (LIAI), CA, USA
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University,Atlanta,GA, USA
The Wistar Institute, Philadelphia, PA, USA
* Corresponding author; email: shane{at}liai.org.
The human genetic disease XLP, caused by mutations in
SH2D1A/SAP, encoding SLAM-associated protein (SAP), is
characterized by an inability to control Epstein-Barr
Virus (EBV) and hypogammaglobulinemia. It is unclear
which aspects of XLP disease are specific to herpesvirus
infection and which reflect general immunological
functions performed by SAP. We examined SAP- mice during
a chronic LCMV infection, specifically to address the
question: which SAP-deficiency immunological problems
are general, and which are EBV-specific? Illness, weight
loss, and prolonged viral replication were much more
severe in SAP- mice. Aggressive immunopathology was
observed. This inability to control chronic LCMV was
associated with both CD8 T cell and B cell response
defects. Importantly, we demonstrate that SAP- CD8 T
cells are the primary cause of the immunopathology and
clinical illness, as depletion of CD8 T cells blocked
disease. This is the first direct demonstration of SAP-
CD8 T cell mediated immunopathology, confirming thirty
years of XLP clinical observations and indirect
experimentation. In addition, germinal center formation
was extremely defective in chronically infected SAP-
animals, and hypogammaglobulinemia was observed. These
findings in a chronic viral infection mouse model
recapitulate key features of human XLP and clarify SAP's
critical role regulating both cellular and humoral
immunity.
