Immune Cell Profiling the Peripheral Blood of Heart and Lung Transplant Recipients
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2022
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Melbourne Authors
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Paediatrics (RCH)
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PhD thesis
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Open Access
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© 2022 Sedigheh Jalali
Abstract
Protection against disease requires cells from both the innate and adaptive arms of the human immune system. The impact of disease is often significantly influenced by age. In humans, newborns have an immature immune system; thus, they are more susceptible to some infectious diseases such as influenza and respiratory syncytial virus (RSV). Whereas the immature immune system in infants below 14 months of age is advantageous in some settings such as heart transplants recipients, even if the donor and recipient are ABO mismatched. Later on in life, the immune system wanes and this renders elderly people more susceptible to diseases such as infections and cancers. This has recently been exemplified by COVID-19, which is more fatal in older age groups, particularly in individuals with other co-morbidities. Therefore, understanding the composition of the human immune system throughout life is crucial if we are to endeavor to manipulate the immune response for treating human disease. In this thesis, we used high-dimensional spectral flow cytometric analysis to generate an immune cell atlas encompassing more than 50 populations of immune cells from individuals aged below 1 month to 75 years of age and then we assessed changes to the immune system in adult lung transplant recipients (LTRs) and paediatric heart transplant recipients (HTRs). Specifically, the human immune landscape undergoes major changes early on in life and this likely influences how the body responds to certain diseases such as solid organ transplantation. Our results showed that naive T cells were replaced with different proportions of memory cell subsets in healthy people throughout life, while the trends were different among children who received heart transplantation. Moreover, the proportion of MAIT cells, gamma delta T cells and plasmablasts in healthy individuals were low in the first few years of life, peaking in teenagers, and declining in elderly. While in contrast, we found increased MAIT cells in peripheral blood of paediatric HTRs particularly infants below 2 years old who did not develop HTx rejection and increased gamma delta T cells in those who developed HTx rejection. Furthermore, we identified several immune cell biomarkers of HTx rejection. For example, CD16 on the surface of gamma delta T cells imbues these cells the ability to perform antibody-dependent cellular cytotoxicity (ADCC), a process which normally exhibit by natural killer (NK) cells. Our results revealed that gamma delta T cells from paediatric HTRs expressed lower levels of CD16 post-HTx, particularly in recipients that showed no sign of rejection, suggesting that gamma delta T cells could play a protective role via CD16-mediated activation. Moreover, we found that among those immunosuppressive drugs which organ transplant recipients routinely take, only calcineurin inhibitors blocked the activation of gamma delta T cells via CD16-mediated ADCC. These findings may lead to better detection of HTx rejection, modify the current treatments for disease and ultimately improved outcomes for solid organ transplant recipients. Altogether, this thesis provides the first comprehensive study of the immune system throughout ontogeny, which not only provides a foundation for understanding changes to the immune system in the context of heart and lung transplantation, but also for many other human diseases.
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Heart transplantation, Lung transplantation, gamma delta T cells, ADCC, deep immune profiling, human immune system ontogeny, CD16, rejection, paediatric, unconventional T cells, immunosuppressive drugs, blood biomarkers, high-dimensional flow cytometry, peripheral blood immune cell atlas