Immune regeneration in irradiated mice is not impaired by the absence of DPP9 enzymatic activity

Margaret G Gall,Mark D Gorrell,Hui Emma Zhang,Adam Cook,Christopher J Jolly,Quintin Lee,Ben Roediger,Geoffrey W Mccaughan

doi:10.1038/s41598-019-43739-w

Margaret G Gall, Mark D Gorrell + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-43739-w

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Abstract

The ubiquitous intracellular protease dipeptidyl peptidase 9 (DPP9) has roles in antigen presentation and B cell signaling. To investigate the importance of DPP9 in immune regeneration, primary and secondary chimeric mice were created in irradiated recipients using fetal liver cells and adult bone marrow cells, respectively, using wild-type (WT) and DPP9 gene-knockin (DPP9S729A) enzyme-inactive mice. Immune cell reconstitution was assessed at 6 and 16 weeks post-transplant. Primary chimeric mice successfully regenerated neutrophils, natural killer, T and B cells, irrespective of donor cell genotype. There were no significant differences in total myeloid cell or neutrophil numbers between DPP9-WT and DPP9S729A-reconstituted mice. In secondary chimeric mice, cells of DPP9S729A-origin cells displayed enhanced engraftment compared to WT. However, we observed no differences in myeloid or lymphoid lineage reconstitution between WT and DPP9S729A donors, indicating that hematopoietic stem cell (HSC) engraftment and self-renewal is not diminished by the absence of DPP9 enzymatic activity. This is the first report on transplantation of bone marrow cells that lack DPP9 enzymatic activity.

Highlights

The ubiquitous intracellular post-proline serine protease dipeptidyl peptidase 9 (DPP9) belongs to the DPP4 gene family, which includes four atypical serine proteases: DPP4, fibroblast activation protein (FAP), DPP8 and DPP91,2
Fetal liver cells were used as donor cells for primary bone marrow reconstitution chimeras because DPP9S729A mice die within 24 h of birth[15,16,17], precluding the availability of an adult source of DPP9-defective hematopoietic stem cells (HSC)
Fetal liver cells deficient in DPP9 enzymatic activity were analyzed for viability and the phenotypic content of stem and progenitor cells, which are necessary for immune regeneration

Summary

Introduction

The ubiquitous intracellular post-proline serine protease dipeptidyl peptidase 9 (DPP9) belongs to the DPP4 gene family, which includes four atypical serine proteases: DPP4, fibroblast activation protein (FAP), DPP8 and DPP91,2. DPP4 is expressed by immune cells of both the myeloid and lymphoid lineages[19,20]. Whether the absence of DPP9 enzymatic activity affects short-term and long-term repopulation of immune cells of the lymphoid or myeloid lineages is underexplored. Myeloid and lymphoid cell types are present and, in the long term (4 months), whether the reconstituted HSC are functional[26,27,28]. Neutrophils and macrophages are the first cell types to recover after combined myelo-ablative irradiation and fetal liver or adult bone marrow cell transplant. These cells appear in the first few days after transplant, followed closely by B cells. A small proportion of host T cells resist the effects of irradiation and expand in the post-irradiated environment, and can be detected within three weeks of transplant, while donor T cells usually become detectable 4 to 5 weeks after transplantation[29]

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