期刊
JOURNAL OF IMMUNOLOGY
卷 196, 期 1, 页码 135-143出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1403060
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- Deakin University
The IL-2 receptor gamma common (IL-2R gamma c) chain is the shared subunit of the receptors for the IL-2 family of cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphopoiesis. Inactivating mutations in human IL-2R gamma c result in SCID, a primary immunodeficiency characterized by greatly reduced numbers of lymphocytes. This study used bioinformatics, expression analysis, gene ablation, and specific pharmacologic inhibitors to investigate the function of two putative zebrafish IL-2R gamma c paralogs, il-2r gamma c.a and il-2r gamma c.b, and downstream signaling components during early lymphopoiesis. Expression of il-2r gamma c.a commenced at 16 h post fertilization (hpf) and rose steadily from 4-6 d postfertilization (dpf) in the developing thymus, with il-2r gamma c. a expression also confirmed in adult T and B lymphocytes. Transcripts of il-2r gamma c.b were first observed from 8 hpf, but waned from 16 hpf before reaching maximal expression at 6 dpf, but this was not evident in the thymus. Knockdown of il-2r gamma c. a, but not il-2r gamma c.b, substantially reduced embryonic lymphopoiesis without affecting other aspects of hematopoiesis. Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas ablation of zebrafish Stat5.1 and pharmacologic inhibition of PI3K and MEK also produced significant but smaller effects. Ablation of il-2r gamma c.a was further demonstrated to lead to an absence of mature T cells, but not B cells in juvenile fish. These results indicate that conserved IL-2R gamma c signaling via JAK3 plays a key role during early zebrafish lymphopoiesis, which can be potentially targeted to generate a zebrafish model of human SCID.
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