SAP expression in T cells, not in B cells, is required for humoral immunity

doi:10.1073/pnas.0710698105

SAP expression in T cells, not in B cells, is required for humoral immunity

*Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, QC, Canada H2W 1R7;
^†Department of Medicine, University of Montréal, Montréal, QC, Canada H3T IJ4; and
^‡Department of Medicine, McGill University, Montréal, QC, Canada H3G IY6

Edited by Arthur Weiss, University of California School of Medicine, San Francisco, CA, and approved December 10, 2007 (received for review November 10, 2007)

Abstract

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.

Footnotes

^§To whom correspondence should be addressed. E-mail: veillea{at}ircm.qc.ca
Author contributions: A.V., S.Z., X.S., Z.D., D.D., and M.-C.Z. designed research; A.V., S.Z., X.S., Z.D., D.D., and M.-C.Z. performed research; A.V., S.Z., X.S., Z.D., D.D., and M.-C.Z. analyzed data; and A.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710698105/DC1.