Identification of a transcription factor that controls cytotoxic T lymphocyte in a murine model of GVHD

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591662
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Nara Medical University
• Principal Investigator: MIYAGAWA Fumi 奈良県立医科大学, 医学部, 助教 (00346024)
• Co-Investigator(Kenkyū-buntansha): ASADA Hideo 奈良県立医科大学, 皮膚科, 教授 (60252681)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: CD8 T cell / effector function / IL-15 / gamma c cytokine / TCR / GVHD

Outline of Final Research Achievements

We previously reported that γc-cytokines, especially IL-15, play a critical role in determining whether or not CD8 cells exert cytotoxic activity in an experimental GVHD mouse model. We then hypothesized that cooperation between γc-cytokine and TCR/co-stimulation signaling is critical in enabling the transition of naive CD8 T cells into effector cells. In this study, we demonstrated that the transcription factor interferon regulatory factor 8 (IRF8) is persistently activated by these two signals in CD8 T cells. Blocking these signaling pathways by either a ZAP70 inhibitor or a Jak3 inhibitor abrogated IRF8 upregulation and inhibited effector differentiation in CD8 T cells. In an experimental GVHD mouse model, IRF8 deficient CD8 T cells failed to differentiate into cytotoxic T cells, causing reduced pathology. Together, our work shows that IRF8 integrates the TCR/co-stimulation and γc-cytokine signaling pathways and drives transition of naive CD8 T cells to effector cells.

Free Research Field

皮膚免疫学