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Normal Development and Activation but Altered Cytokine Production of Fyn-Deficient CD4⁺ T Cells¹

Alusha A. Mamchak^*, Brandon M. Sullivan^,, Baidong Hou^*, Linda M. Lee^*, Julia K. Gilden, Matthew F. Krummel, Richard M. Locksley^*,, and Anthony L. DeFranco^2,*

^* Department of Microbiology and Immunology, Department of Pathology, Department of Medicine, and The Howard Hughes Medical Institute, University of California, San Francisco, CA 94143

The Src family kinase Fyn is expressed in T cells and has been shown to phosphorylate proteins involved in TCR signaling, cytoskeletal reorganization, and IL-4 production. Fyn-deficient mice have greatly decreased numbers of NKT cells and have thymocytes and T cells with compromised responses following Ab crosslinking of their TCRs. Herein we have addressed the role of Fyn in peptide/MHC class II-induced CD4⁺ T cell responses. In Fyn-deficient mice, CD4⁺ T cells expressing the DO11.10 TCR transgene developed normally, and the number and phenotype of naive and regulatory DO11.10⁺CD4⁺ T cells in the periphery were comparable with their wild-type counterparts. Conjugation with chicken OVA peptide 323–339-loaded APCs, and the subsequent proliferation in vitro or in vivo of DO11.10⁺ Fyn-deficient CD4⁺ T cells, was virtually indistinguishable from the response of DO11.10⁺ wild-type CD4⁺ T cells. Proliferation of Fyn-deficient T cells was not more dependent on costimulation through CD28. Additionally, we have found that differentiation, in vitro or in vivo, of transgenic CD4⁺ Fyn-deficient T cells into IL-4-secreting effector cells was unimpaired, and under certain conditions DO11.10⁺ Fyn-deficient CD4⁺ T cells were more potent cytokine-producing cells than DO11.10⁺ wild-type CD4⁺ T cells. These data demonstrate that ablation of Fyn expression does not alter most Ag-driven CD4⁺ T cell responses, with the exception of cytokine production, which under some circumstances is enhanced in Fyn-deficient CD4⁺ T cells.

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 The Joseph Marino Research Award from the Crohn’s & Colitis Foundation of America (to A.A.M.) and National Institutes of Health Grants P01 AI-35297 (to A.L.D.), AI-26918 (to R.M.L.), and R01 AI-052116 (to M.F.K.).

² Address correspondence and reprint requests to Dr. Anthony L. DeFranco, University of California, San Francisco, Box 0414, HSE-1001F, San Francisco, CA 94143. E-mail address: Anthony.Defranco{at}ucsf.edu

³ Abbreviations used in this paper: SLAM, signaling lymphocyte activation molecule; CMTMR, 5-(and 6)-(((4-chloromethyl)benzoyl)amino)tetramethylrhodamine; DDAO, 7-hydroxy-9H-(I,3-dichloro-9,9-dimethylacridin-2-one); [³H]TdR, [methyl-³H]thymidine; Ovap_323–339, chicken OVA peptide 323–339; SAP, SLAM-associated protein; WASp, Wiskott-Aldrich syndrome protein.

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The JI 2008 181: 5179-5180. [Full Text]