Long-lived plasma cells and memory B cells are the primary cellular components of long-term humoral immunity and as such are vitally important for the protection afforded by most vaccines. The SAP gene has been identified as the genetic locus responsible for X-linked lymphoproliferative disease, a fatal immunodeficiency1,2,3,4. Mutations in SAP have also been identified in some cases of severe common variable immunodeficiency disease5,6. The underlying cellular basis of this genetic disorder remains unclear. We have used a SAP knockout mouse model system to explore the role of SAP in immune responses. Here we report that mice lacking expression of SAP generate strong acute IgG antibody responses after viral infection, but show a near complete absence of virus-specific long-lived plasma cells and memory B cells, despite the presence of virus-specific memory CD4+ T cells. Adoptive transfer experiments show that SAP-deficient B cells are normal and the defect is in CD4+ T cells. Thus, SAP has a crucial role in CD4+ T-cell function: it is essential for late B-cell help and the development of long-term humoral immunity but is not required for early B-cell help and class switching.
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Coffey, A. J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genet. 20, 129–135 (1998)
Morra, M. et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu. Rev. Immunol. 19, 657–682 (2001)
Nichols, K. E. et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc. Natl Acad. Sci. USA 95, 13765–137670 (1998)
Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998)
Morra, M. et al. Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. Blood 98, 1321–1325 (2001)
Nistala, K. et al. X-linked lymphoproliferative disease: three atypical cases. Clin. Exp. Immunol. 126, 126–130 (2001)
Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998)
Whitmire, J. K., Asano, M. S., Murali-Krishna, K., Suresh, M. & Ahmed, R. Long-term CD4 Th1 and Th2 memory following acute lymphocytic choriomeningitis virus infection. J. Virol. 72, 8281–8288 (1998)
Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998)
Homann, D., Teyton, L. & Oldstone, M. B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nature Med. 7, 913–919 (2001)
Slifka, M. K., Matloubian, M. & Ahmed, R. Bone marrow is a major site of long-term antibody production after acute viral infection. J. Virol. 69, 1895–1902 (1995)
Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997)
O'Connor, B. P., Cascalho, M. & Noelle, R. J. Short-lived and long-lived bone marrow plasma cells are derived from a novel precursor population. J. Exp. Med. 195, 737–745 (2002)
Czar, M. J. et al. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proc. Natl Acad. Sci. USA 98, 7449–7454 (2001)
Wu, C. et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nature Immunol. 2, 410–414 (2001)
Durandy, A. & Honjo, T. Human genetic defects in class-switch recombination (hyper-IgM syndromes). Curr. Opin. Immunol. 13, 543–548 (2001)
Banchereau, J. et al. The CD40 antigen and its ligand. Annu. Rev. Immunol. 12, 881–922 (1994)
Shlapatska, L. M. et al. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J. Immunol. 166, 5480–5487 (2001)
Tangye, S. G., van de Weerdt, B. C. M., Avery, D. T. & Hodgkin, P. D. CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2. Eur. J. Immunol. 32, 1640–1649 (2002)
Latour, S. et al. Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nature Immunol. 2, 681–690 (2001)
van Essen, D., Kikutani, H. & Gray, D. CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature 378, 620–623 (1995)
Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999)
Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. & Cyster, J. G. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 1123–1134 (1999)
Campbell, D. J., Kim, C. H. & Butcher, E. C. Separable effector T cell populations specialized for B cell help or tissue inflammation. Nature Immunol. 2, 876–881 (2001)
Kim, C. H. et al. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193, 1373–1381 (2001)
MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994)
Grierson, H. L., Skare, J., Hawk, J., Pauza, M. & Purtilo, D. T. Immunoglobulin class and subclass deficiencies prior to Epstein-Barr virus infection in males with X-linked lymphoproliferative disease. Am. J. Med. Genet. 40, 294–297 (1991)
Sumegi, J. et al. Correlation of mutations of the SH2D1A gene and Epstein–Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood 96, 3118–3125 (2000)
Ahmed, R., Salmi, A., Butler, L. D., Chiller, J. M. & Oldstone, M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160, 521–540 (1984)
Slifka, M. K. & Ahmed, R. Limiting dilution analysis of virus-specific memory B cells by an ELISPOT assay. J. Immunol. Methods 199, 37–46 (1996)
We thank L. Mijares for technical assistance, and J. Gibson Lanier and D. Barber for expertise. This work was supported by intramural and extramural NIH funding. S.C. is a Cancer Research Institute postdoctoral fellow.
The authors declare that they have no competing financial interests.
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Crotty, S., Kersh, E., Cannons, J. et al. SAP is required for generating long-term humoral immunity. Nature 421, 282–287 (2003). https://doi.org/10.1038/nature01318
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