Upregulation of GRAIL is associated with impaired CD4 T cell proliferation in sepsis.
The loss of numbers and functionality of CD4 T cells is observed in sepsis; however, the mechanism remains elusive. Gene related to anergy in lymphocytes (GRAIL) is critical for the impairment of CD4 T cell proliferation. We therefore sought to examine the role of GRAIL in CD4 T cell proliferation during sepsis. Sepsis was induced in 10-wk-old male C57BL/6 mice by cecal ligation and puncture. Splenocytes were isolated and subjected to flow cytometry to determine CD4 T cell contents. CD4 T cell proliferation was assessed by CFSE staining, and the expression of GRAIL in splenocytes was measured by immunohistochemistry, real-time PCR, and flow cytometry. The expressions of IL-2 and early growth response-2 were determined by real-time PCR. As compared with shams, the numbers of CD4 T cells were significantly reduced in spleens. Septic CD4 T cells were less efficient in proliferation than shams. The IL-2 expression was significantly reduced, whereas the GRAIL expression was significantly increased in septic mice splenocytes as compared with shams. The small interfering RNA-mediated knockdown of GRAIL expression re-established the CD4 T cell proliferation ability ex vivo. Similarly, the treatment with recombinant murine IL-2 to the septic CD4 T cells restored their proliferation ability by downregulating GRAIL expression. Our findings reveal a novel association of the increased GRAIL expression with impaired CD4 T cell proliferation, implicating an emerging therapeutic tool in sepsis.
Center for Translational Research, Feinstein Institute for Medical Research, Manhasset, NY 11030.
Monowar
M
Aziz
Weng-Lang
WL
Yang
Shingo
S
Matsuo
Archna
A
Sharma
Mian
M
Zhou
Ping
P
Wang
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D007120:Immunochemistry; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D007376:Interleukin-2; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases