Novel mechanisms of graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT)

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H06537
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Yamagata University
• Principal Investigator: TOBAI TOMOMI 山形大学, 医学部, 講師 (40802111)
• Research Collaborator: Pavan Reddy
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: 移植片対宿主病 / NLRP6 / T細胞 / 同種移植

Outline of Final Research Achievements

NOD-like receptor family pyrin domain containing 6 (NLRP6) plays an important role in regulating gut microbiota and homeostasis. However, whether NLRP6 regulates T cell functions remains unknown. We found that naive T cells express NLRP6 but the absence of NLRP6 did not affect the numbers and the subpopulation of T cells, such as regulatory T cells. The expression of NLRP6 in T cells was dramatically increased following stimulation with anti-CD3/CD28 antibodies. NLRP6 deficient T cells exhibited significantly greater proliferation after non-specific T cell receptor stimulation as well as mixed lymphocyte reaction (MLR). We also demonstrated that the absence of NLRP6 on donor T cells exacerbated graft-versus -host disease (GVHD) in multiple irradiated and non-irradiated BMT models. We suggest that NLRP6 is a potentially novel negative regulator of T cell responses, and maybe a useful target to mitigate GVHD.

Free Research Field

造血幹細胞移植、血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、炎症反応においてNLRP6がインフラマゾーム依存性メカニズムを持つだけでなく、非依存性メカニズムを持っていることを明らかにしたことにより、NLRP6が種々の免疫反応において多種多彩な機能を持つことを明確に示すことができた。NLRP6の免疫細胞における機能解析を発展させる事で、敗血症などの炎症性疾患のみならず移植片対宿主病や自己免疫疾患、さらには悪性腫瘍内の微小環境下における免疫抑制機構の解明にも貢献すると考えられる。NLRP6の制御機構を明らかにする事で、将来的な免疫チェックポイントや免疫抑制剤の開発につながる可能性がある。