Involvement of SLC17A9-dependent vesicular exocytosis in the mechanism of ATP release during T cell activation.
Recent reports have shown that T cell receptor (TCR)-dependent ATP release from T cells is involved in production of interleukin-2 (IL-2) through activation of P2 receptors. Stimulation of TCR induces ATP release from T cells through gap junction hemichannels and maxianion channels, at least in part. However, the mechanisms of ATP release from activated T cells are not fully understood. Here, we studied the mechanisms of ATP release during TCR-dependent T cell activation by investigating the effects of various inhibitors on TCR-dependent ATP release from murine T cells. We found that not only anion channel and gap junction hemichannel inhibitors, but also exocytosis inhibitors suppressed the ATP release. These results suggest that ATP release from murine T cells is regulated by various mechanisms, including exocytosis. An inhibitor of exocytosis, bafilomycin A, significantly blocked TCR signaling, such as Ca(2+) elevation and IL-2 production. Furthermore, bafilomycin A, ectonucleotidase, and P2Y(6) receptor antagonist significantly inhibited production of pro-inflammatory cytokines from external antigen-restimulated splenocytes, indicating that vesicular exocytosis-mediated purinergic signaling has a significant role in TCR-dependent cytokine production. We also detected vesicular ATP in murine T cells and human T lymphoma Jurkat cells, both of which also expressed mRNA of SLC17A9, a vesicular nucleotide transporter. Knockdown of SLC17A9 in Jurkat cells markedly reduced ATP release and cytosolic Ca(2+) elevation after TCR stimulation, suggesting involvement of SLC17A9-dependent vesicular exocytosis in ATP release and T cell activation. In conclusion, vesicular exocytosis of ATP appears to play a role in T cell activation and immune responses.
Tokunaga
Akihiro
A
Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi Chiba, Japan.
Tsukimoto
Mitsutoshi
M
Harada
Hitoshi
H
Moriyama
Yoshinori
Y
Kojima
Shuji
S
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D002118:Calcium / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D005089:Exocytosis; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D033704:Nucleotide Transport Proteins / Q000737:chemistry*; D011948:Receptors, Antigen, T-Cell; D013601:T-Lymphocytes / Q000378:metabolism*
D007376:Interleukin-2; D033704:Nucleotide Transport Proteins; D011948:Receptors, Antigen, T-Cell; C529437:Slc17a9 protein, human; D000255:Adenosine Triphosphate; D002118:Calcium
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