Role of post-transcriptional gene regulation by Roquin proteins in the prevention of autoinflammation and pancreatic cancer

Raj, Timsse (2022): Role of post-transcriptional gene regulation by Roquin proteins in the prevention of autoinflammation and pancreatic cancer. Dissertation, LMU München: Medizinische Fakultät

Abstract

Summary Post-transcriptional gene regulation by the RNA-binding-proteins Roquin-1/2 and Regnase-1 is important for the maintenance of immune homeostasis and controls T helper cell fate decisions. Deficiencies in one or all of these proteins lead to aberrant activation of the immune system and the development of autoimmunity and autoinflammation. To date investigations have mainly focused on T cell intrinsic consequences of Roquin-1/2 and/or Regnase-1 loss-of-function. In my research project, I demonstrated that Roquin-1/2 loss-of-function has T cell intrinsic and extrinsic effect, whereas Regnase-1 acted predominantly in a T cell intrinsic manner. In adoptive transfer experiments, I showed that DKOT T cells cause bystander activation of WT CD8+ T cells, bystander TFH differentiation of WT CD4+ T cells and concomitant accumulation of GC B cells. TFH cell differentiation did not require IFNγ, IL-6 or ICOS signaling in recipient cells. This effect was independent of SAP signaling but did require interactions with B cells. Furthermore, DKOT cells were able to replace co-stimulatory signals that potently activated bystander T cells, which lacked normal B7-mediated CD28 stimulation. Several molecules that could be responsible for the observed trans-effect were identified in an mRNASeq experiment and CD86 and CD40L were further investigated. The second and third parts of the thesis focused on extrinsic functions of DKOT T cells that caused a spontaneous, inflammation-mediated cancer development in the pancreas. Specifically, I showed that mice with conditional Roquin-1/2 deletion in T cells spontaneously developed pancreas pathology and pre-neoplastic low grade panIN lesions. In these mice, inflammatory CD11b+ Gr1+, TH17 and TFH cells accumulated, both systemically as well as locally in the pancreas draining lymph nodes and Ly6G+ neutrophils infiltrated into pancreas tissue. In the context of acinar cell-specific oncogenic KrasG12D signaling DKOT T cell-mediated local accumulation of inflammatory cells in the pancreas microenvironment accelerated cancer development and progression. I described a role of Roquin proteins in the prevention of tissue inappropriate expression of G-CSF in CD4+ T cells by direct repression of the G-CSF encoding mRNA through its 3’UTR. In conclusion, in this work I described a mouse model of spontaneous pancreas cancer development that is driven by DKOT TH17 cells via the IL-17A/G-CSF/neutrophil axis and provided evidence of a T cell extrinsic role of post-transcriptional gene regulation in the prevention of pathology.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 22. Juni 2022
• 1. Bericht­erstatter:in: Heissmeyer, Vigo