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* Trudeau Institute, Saranac Lake, NY 12983; and
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
Ab is a crucial component of protective immunity to infection, but Ab responses do not proceed normally when defects occur in a protein called signaling lymphocytic activation molecule-associated protein (SAP). To explain this Ab defect, we analyzed B cell and plasma cell responses under conditions of SAP deficiency. Our results demonstrate that SAP-deficient (SAP knockout (KO)) mice have a profound CD4 T cell-intrinsic defect in generating Ag-specific plasma cells following challenge with model Ags or influenza virus, resulting in low Ag-specific Ab titers. We also show that SAP is required in CD4 T cells for normal division and expansion of B cells. These B cell and plasma cell defects were observed during the expansion phase of the primary immune response, indicating early defects in Th cell activity. In fact, additional experiments revealed a nearly complete lack of T cell help for B cells in SAP KO mice. Our work suggests that the ability of SAP to promote T-dependent humoral immune responses is important for antiviral immunity because mice lacking SAP are unable to prevent high dose secondary influenza infection, and because passive transfer of IgG in immune serum from wild-type, but not SAP KO mice can protect mice from an otherwise lethal influenza infection. Overall, our results demonstrate that SAP is required in CD4 T cells for their ability to help B cell responses and promote influenza-specific immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI22125-17 (to S.L.S.), AI46530 (to S.L.S.), and AI066684-01 (to C.K.), and by the Trudeau Institute.
2 Address correspondence and reprint requests to Dr. Cris Kamperschroer, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983.
3 Abbreviations used in this paper: SLAM, signaling lymphocytic activation molecule; SAP, SLAM-associated protein; AFC, Ab-forming cell; EID50, 50% egg infectious dose; GC, germinal center; HEL, hen egg lysozyme; i.n., intranasally; KO, knockout; LCMV, lymphocytic choriomeningitis virus; BM, bone marrow; MLN, mediastinal lymph node; NP, 4-hydroxy-3-nitrophenylacetyl; PA, polymerase; PNA, peanut lectin agglutinin; PR8, Puerto Rico/8; WT, wild type; XLP, X-linked lymphoproliferative disease.
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  C. Kamperschroer, D. M. Roberts, Y. Zhang, N.-p. Weng, and S. L. Swain SAP Enables T Cells to Help B Cells by a Mechanism Distinct from Th Cell Programming or CD40 Ligand Regulation J. Immunol., September 15, 2008; 181(6): 3994 - 4003. [Abstract] [Full Text] [PDF]
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 A. Veillette, S. Zhang, X. Shi, Z. Dong, D. Davidson, and M.-C. Zhong SAP expression in T cells, not in B cells, is required for humoral immunity PNAS, January 29, 2008; 105(4): 1273 - 1278. [Abstract] [Full Text] [PDF]
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C. C. Kemball, C. D. Pack, H. M. Guay, Z.-N. Li, D. A. Steinhauer, E. Szomolanyi-Tsuda, and A. E. Lukacher The Antiviral CD8+ T Cell Response Is Differentially Dependent on CD4+ T Cell Help Over the Course of Persistent Infection J. Immunol., July 15, 2007; 179(2): 1113 - 1121. [Abstract] [Full Text] [PDF]
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