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* Trudeau Institute, Saranac Lake, NY 12983; and
DNA Array Unit and
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224
Genetic mutations disrupting the function of signaling lymphocytic activation molecule-associated protein (SAP) lead to T cell intrinsic defects in T cell-dependent Ab responses. To better understand how SAP enables Th cells to help B cells, we first assessed whether molecules important for B cell help are dysregulated in SAP-deficient (SAP knockout (KO)) mice. CD40 ligand (CD40L) expression was enhanced on unpolarized SAP KO T cells; however, Th2 polarization returned their CD40L expression to wild-type levels without rescuing their ability to help B cells. CD40L also localized normally to the site of contact between SAP KO T cells and Ag-bearing B cells. Finally, CD40L-deficient Th cells and SAP KO Th cells differed in their abilities to help B cells in vitro. These data argue that Ab defects caused by SAP deficiency do not result from a loss of CD40L regulation or CD40L function on CD4 T cells. SAP KO Th cells additionally displayed normal patterns of migration and expression of ICOS and CXCR5. Global gene expression was remarkably similar in activated SAP KO vs wild-type T cells, prompting us to investigate whether SAP is necessary for "programming" T cells to become B cell helpers. By restricting SAP expression during differentiation, we determined that SAP is not required during the first 5 days of T cell activation/differentiation to generate Th cells capable of helping B cells. Instead, SAP is necessary for very late stages of differentiation or, most likely, for allowing Th cells to communicate during cognate T:B interactions.
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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. K.G.B. and N.P.W. were supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Cris Kamperschroer, Pfizer Inc., MS 8274-1406, Eastern Point Road, Groton, CT 06340. E-mail address: Cris.Kamperschroer{at}pfizer.com
3 Abbreviations used in this paper: CD40L, CD40 ligand; TFH, follicular homing T cell; GC, germinal center; HEL, hen egg lysozyme; NP, 4-hydroxy-3-nitrophenylacetyl; SLAM, signaling lymphocytic activation molecule; SAP, SLAM-associated protein; KO, knockout; WT, wild type; LN, lymph node; SA, streptavidin; Teff, effector T cell; AFC, Ab-forming cell; PNA, peanut agglutinin.
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  Q. Chen, J. L. Cannons, J. C. Paton, H. Akiba, P. L. Schwartzberg, and C. M. Snapper A Novel ICOS-Independent, but CD28- and SAP-Dependent, Pathway of T Cell-Dependent, Polysaccharide-Specific Humoral Immunity in Response to Intact Streptococcus pneumoniae versus Pneumococcal Conjugate Vaccine J. Immunol., December 15, 2008; 181(12): 8258 - 8266. [Abstract] [Full Text] [PDF]
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