CD28-induced cytokine production and proliferation by thymocytes are differentially regulated by the p59fyn tyrosine kinase.

The src-family kinases p56lck (Lck) and p59fyn (Fyn) are expressed in T cells and are among the first signaling molecules to be activated downstream of the T cell receptor (TCR). Evidence is emerging that although closely related, these signaling molecules have discrete functions during development, maintenance and activation of peripheral T cells. For example, during thymopoiesis Lck is uniquely able to provide all the signals required for pre-TCRbeta selection, although Fyn can substitute for a subset of these. Positive selection of CD4 single-positive (SP) cells is also critically dependent on the expression of Lck but not Fyn, while differentiation of CD8 SP cells proceeds relatively efficiently in the absence of Lck. In naïve peripheral T cells either Lck or Fyn can transmit TCR-mediated survival signals, and yet only Lck is able to trigger TCR-mediated expansion signals under conditions of lymphopenia. Stimulation of naïve T cells by antigenic stimuli is also severely compromised in the absence of Lck, but more subtly impaired by the absence of Fyn. We discuss recent experiments addressing how these two src-kinase family members interface with downstream signaling pathways to regulate these diverse aspects of T cell behavior.

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The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation

Zamoyska

Basson

Filby

et al. 2003

Immunological Reviews

182

143

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T Cells Expressing Receptors of Different Affinity for Antigen Ligands Reveal a Unique Role for p59fynin T Cell Development and Optimal Stimulation of T Cells by Antigen

Utting

Teh

1998

The Journal of Immunology

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Signaling from the TCR involves the protein tyrosine kinase p59fyn (Fyn). Previous studies have shown that T cell development occurs normally in Fyn−/− mice. In this study, we investigated the requirement for Fyn in the development and function of T cells expressing either the transgenic 2C TCR, with high affinity for its Ag ligand, or the transgenic H-Y TCR, representative of a low affinity TCR. Although Fyn was not essential for positive selection of thymocytes expressing either the 2C or the H-Y TCR, it facilitated the down-regulation of the heat-stable Ag in positively selected CD4−CD8+ thymocytes in both 2C and H-Y mice. Negative selection of thymocytes expressing the H-Y TCR also occurs efficiently in Fyn−/− mice. However, in Fyn−/− mice, there was a preferential survival of thymocytes that expressed higher levels of the CD8 coreceptor and the transgenic TCR. Positively selected CD4−CD8+ thymocytes and peripheral T cells expressing either the 2C or the H-Y TCR differed in their requirement of Fyn for optimal proliferation responses to stimulation by antigenic ligands. Whereas 2C Fyn−/− or 2C Fyn+/+ thymocytes and peripheral T cells responded optimally to stimulation by the specific Ag, H-Y Fyn−/− thymocytes and peripheral T cells were hyporesponsive compared with Fyn+/+ cells. Significantly, in response to a defined low affinity ligand, both 2C Fyn−/− thymocytes and peripheral T cells required Fyn for optimal response to Ag stimulation. Thus, Fyn plays a role during thymocyte development and is required for optimal responses to low affinity/avidity ligands.

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Autoantigen-Specific CD4+CD28low T Cell Subset Prevents Autoimmune Exocrinopathy in Murine Sjögren’s Syndrome

Saegusa

Ishimaru²,

Yanagi³

et al. 2000

The Journal of Immunology

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Organ-specific autoimmune exocrinopathy resembling Sjögren’s syndrome (SS) that spontaneously develops in NFS/sld mutant mice thymectomized 3 day after birth is dependent on Th1-type CD4+ T cells. We previously reported that a cleavage product of 120-kDa α-fodrin may be an important autoantigen in the pathogenesis of SS in both an animal model and the patients. We demonstrate that in an animal model of SS with overt exocrinopathy, a unique CD4+ T cell subset expressing CD28low is dramatically increased in spleen cells before the disease onset, but that the CD4+ T cells of diseased mice were virtually all CD28high. We found that the spleen cells in these mice before the disease onset showed a significant increase in autoantigen-specific T cell proliferation. Analysis of in vitro cytokine production by spleen cells indicated, before the disease onset, severely impaired production of IL-2 and IFN-γ in the animal model, whereas high levels of IL-4 were observed. Expression of cytokine genes, including IL-4, IL-10, and TGF-β, was detected in FACS-sorted CD4+CD28low T cells by RT-PCR analysis. Transfer of CD4+CD28low T cells into the animal model actually prevented the development of autoimmune lesions including autoantibody production. These results suggest that a CD4+CD28low T cell subset that is continuously activated by an organ-specific autoantigen may play a regulatory role in the development of organ-specific autoimmune disease in an animal model of SS.

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CD28-induced cytokine production and proliferation by thymocytes are differentially regulated by the p59fyn tyrosine kinase.

Cited by 3 publications

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The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation

The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation

T Cells Expressing Receptors of Different Affinity for Antigen Ligands Reveal a Unique Role for p59fynin T Cell Development and Optimal Stimulation of T Cells by Antigen

Autoantigen-Specific CD4+CD28low T Cell Subset Prevents Autoimmune Exocrinopathy in Murine Sjögren’s Syndrome

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