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

Abstract

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.

Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells

“…Another explanation, which is not mutually exclusive, is that the different genetic backgrounds of the Blk −/− mice used in the two studies (i.e., 129/Sv in the first study and C57BL/6 in our study) differentially modify the effects of Blk-deficiency. Consistent with this explanation are the reports that Fyn-deficiency has different effects on T cell activation and function depending on the genetic background of the Fyn −/− mouse (42–45). …”

CD45-Csk Phosphatase-Kinase Titration Uncouples Basal and Inducible T Cell Receptor Signaling during Thymic Development

“…Specifically, it has been reported that Fyn is significantly upregulated after the DP stage of thymic development (Olszowy et al, 1995). Although Fyn lacks a non-redundant role in DP thymocytes during basal or inducible TCR signaling (Figure S6; Mamchak et al, 2008; Zamoyska et al, 2003), we hypothesized that Fyn might contribute to signaling differences between DP and SP4 thymocytes in allelic series mice (Figure 4C). …”

Roles of the Src Tyrosine Kinases Lck and Fyn in Regulating γδTCR Signal Strength

“…CD4 + T cells from Fyn −/− DO11.10 αβTCR Tg mice, however, do not display increased proliferation compared to CD4 + T cells from WT DO11.10 αβTCR Tg mice when stimulated, either in vitro or in vivo , with peptide and APCs [20]. Nonetheless, when activated under the appropriate priming conditions, CD4 + T cells from Fyn −/− DO11.10 αβTCR Tg mice produce significantly more IL-4 or IFNγ than CD4 + T cells from WT DO11.10 αβTCR Tg mice [20]. Taken together, these findings suggest that Fyn negatively regulates the αβTCR signaling response.…”

“…This hyperresponsiveness is manifested as enhanced proliferation, increased IL-2 production and more effective cytolytic activity [19]. CD4 + T cells from Fyn −/− DO11.10 αβTCR Tg mice, however, do not display increased proliferation compared to CD4 + T cells from WT DO11.10 αβTCR Tg mice when stimulated, either in vitro or in vivo , with peptide and APCs [20]. Nonetheless, when activated under the appropriate priming conditions, CD4 + T cells from Fyn −/− DO11.10 αβTCR Tg mice produce significantly more IL-4 or IFNγ than CD4 + T cells from WT DO11.10 αβTCR Tg mice [20].…”