SAP expression in T cells, not in B cells, is required for humoral immunity.
SAP (also named SH2D1A) is an intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells. The SAP gene is mutated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by a faulty immune response to Epstein-Barr virus infection. Previous reports documented severe defects in antibody production and germinal center (GC) formation in SAP-deficient humans and mice genetically engineered to lack SAP expression. However, in vitro studies and adoptive transfer experiments provided conflicting data as to whether this phenotype is caused by a functional defect resulting from SAP deficiency in T cells, B cells, or both. Here, we ascertained which cell types are responsible for this humoral immunity defect by using a conditional gene targeting approach. We also thoroughly examined the expression pattern of SAP in normal immune cells by using intracellular flow cytometry. The results showed that expression of SAP in T cells, but not in B cells or NK cells, is required and sufficient for SAP-dependent antibody production and GC formation. These data provide a critical insight into the mechanism by which SAP regulates humoral immunity. They also help elucidate the basis of a severe human immunodeficiency.
Veillette
André
A
Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, QC, Canada. veillea@ircm.qc.ca
Zhang
Shaohua
S
Shi
Xiaochu
X
Dong
Zhongjun
Z
Davidson
Dominique
D
Zhong
Ming-Chao
MC
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002645:Chickens; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018390:Gene Targeting; D006241:Haptens / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D014301:Trinitrobenzenes / Q000276:immunology / Q000378:metabolism; D005719:gamma-Globulins / Q000276:immunology
D006241:Haptens; D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014301:Trinitrobenzenes; D005719:gamma-Globulins