Skin transplantation in a mouse model of naïve T-cell deficiency

Gumienny, Aleksandra Maria. Skin transplantation in a mouse model of naïve T-cell deficiency. 2016, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12986

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Coronin 1 is one of seven mammalian coronin family members that is preferentially expressed in hematopoietic cells and brain tissue (Ferrari et al. 1999; Jayachandran et al. 2014). It was initially discovered in macrophages where it is involved in Mycobacterium tuberculosis pathogenesis and survival (Ferrari et al. 1999). Interestingly, analysis of coronin 1-deficient mice showed a drastic reduction in the numbers of T cells in the periphery (Föger et al. 2006; Shiow et al. 2008; Haraldsson et al. 2008; Mueller et al. 2008). However, segregation and development of T cells in the thymus showed no significant changes when compared with wild type mice (Mueller et al. 2008). Recent data demonstrate that despite the paucity in naïve T cells, coronin 1-deficient mice are resistant to infections but fail to induce autoimmune diseases (Tchang et al. 2013; Haraldsson et al. 2008; Shiow et al. 2008; Siegmund et al. 2011). The physiological relevance of coronin 1 deficiency in allorejection is yet to be discovered, however, the importance of T cells in this process suggests a critical role for coronin 1. When organs are transplanted between members of the same species, an immune response to such a graft develops alloreactivity. It consists of the same mechanism as an immune response for defense against pathogens but it is mediated against differences in major histocompatibility complexes (MHC) class I and II molecules between the host and the donor (Goldsby et al. 2002).
The goal of my project was to dissect the ability of coronin 1-deficient T cells to recognize foreign MHC complexes and to reject the allograft. I focused on finding the mechanisms that allow coronin 1-deficent mice to keep the graft while at the same time drive the immunity against infection. To this end, I combined skin transplantation experiments with in-depth in vitro analysis.
Interestingly, we found prolonged survival of Balb/c skin transplanted onto coronin 1-deficient BL/6 recipients. Further investigations showed tolerance induction in a minor mismatch setting where BL/6 skin presenting minor histocompatibility antigens from Balb/c were transplanted onto coronin 1-deficient mice. This could be the outcome of reduced frequency and/or impaired activation of T cells in the absence of coronin 1. However, despite increasing coronin 1-deficient CD4+ T cells numbers, we could not induce rejection in Rag2-/- mice transplanted with bm12Rag2-/- skin. Although the retained lower counts of CD4+ T cells could indicate a defect in proliferation or antigen recognition after skin transplantation, further in vitro experiments suggested that coronin 1-deficient T cells were able to recognize antigen through the T cell receptor (TCR) and respond, could become activated and could proliferate. Furthermore, cytokines and cell markers analysis suggest that coronin 1-deficient T cells were under the stress of high activation (IFNγhi, CD5hi, IL-7Rlo) and intense proliferation (Ki-67hi) that could cause exhaustion (PD-1hi) and consequently lead to their death (FasL). As the same markers were not changed in the thymus of coronin 1-deficient mice and the mice could produce recent thymic emigrants this can provide insight into the time point at which coronin 1 is essential for T cells’ survival. In-depth analysis of T cells in vitro and in vivo confirmed the different impact of coronin 1-deficiency in CD8+ and CD4+ T cells, as the prolonged graft survival resembled the depletion of CD4+ T cells in skin transplantation model (Goldsby et al. 2002). In a CD4+ T cell-dependent model, where bm12Rag2-/- skin was transplanted onto coronin 1-deficient mice, we observed acceptance of the graft. What is more, the bm1 (CD8-dependent) skin was rejected in coronin 1-deficient recipients upon transplantation. This absence or delay in rejection in coronin 1-deficient mice caused by induction of tolerance may be due to elevated rate of regulatory T cells (Tregs), the suppressive abilities of conventional CD4+ T cells or combination of these. Finding increased frequencies of Tregs in the coronin 1-deficient mice, compared to wild type mice, supported this statement. In-depth analysis of regulatory T cells in coronin 1-deficient mice showed no difference in suppressive abilities compared with wild type cells. Moreover, we demonstrated that the cells did not generate or proliferate better in coronin 1-deficient mice. Nevertheless, their superior survival over conventional coronin 1-deficient CD4+ T cells in vitro could explain their higher frequencies and could be linked to enhanced expression of PD-1. This, in turn, promotes apoptosis in antigen-specific T cells while increasing survival of Tregs (Francisco, Sage, and Sharpe 2010). Overall, the data suggests a critical role of coronin 1 in T cell-mediated allograft rejection. However, its precise function and mechanistic details are subject for further study.
Advisors:Pieters, Jean and Rolink, Antonius G.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)
UniBasel Contributors:Pieters, Jean and Rolink, Antonius G.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12986
Thesis status:Complete
Number of Pages:1 Online-Ressource (165 Seiten)
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Last Modified:06 Apr 2019 04:30
Deposited On:05 Apr 2019 08:57

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