UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Senescence surveillance: the interplay between the immune system and senescent cells

Pereira, Branca; (2019) Senescence surveillance: the interplay between the immune system and senescent cells. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[img]
Preview
Text
Pereira_ID_thesis.pdf

Download (20MB) | Preview

Abstract

Aging is the single common risk factor for a variety of diseases including Alzheimer´s, heart disease and cancer. Cellular senescence and the accumulation of senescent cells with age are considered the underlying causes of aging. Due to their potential involvement in age-related diseases, eliminating senescent cells and attenuating the senescence-associated secretory phenotype (SASP) have recently emerged as attractive strategies aiming to reverse or delay the onset of such diseases. Although recent studies indicate that senescent cells may be targeted by the immune system, they are unable to explain why senescent cells accumulate with age and at sites of age-related pathologies. Immune cells also exhibit altered functions with age and it has been suggested that the accumulation of senescent cells might be due to a defective immune surveillance with age. Nevertheless, to our knowledge, no studies have been done to address how immunosenescence affects the surveillance of senescent cells, mainly because these two subjects are often discussed independently. The overall goal of this work was to investigate the interplay between the immune system and senescent cells. Using an autologous in vitro system with skin-explanted fibroblasts and human peripheral lymphocytes isolated from the same donors, the interactions between immune cells and fibroblasts induced to senescence could be investigated. A novel mechanism of immune evasion was identified and dependent on the expression of HLA-E by senescent cells, a non-classical MHC molecule that protects senescent cells from immune clearance via the interaction with the inhibitory Natural Killer (NK) receptor NKG2A, expressed by NK and cytotoxic T cells. Using a monoclonal antibody to block the interaction of HLA-E with NKG2A in vitro, we could successfully enhance the clearance of senescent cells by the immune system. Mechanistically, it was demonstrated that HLA-E expression on senescent cells is regulated by p38MAPK and induced after exposure to inflammatory cytokines, such as IL-6. Interestingly, it was found that NK cell receptors such as NKG2A and NKG2D were predominantly expressed by a subset of CD8+ T cells with a highly differentiated phenotype, which are expanded with age. To investigate the biological significance of the expression of NK cell receptors by differentiated CD8+ T cells, functional and transcriptomic studies were performed. It was found that highly differentiated CD8+ T cells acquire phenotypic and functional properties resembling NK cells, which are evident at the transcriptomic level by an overexpression of genes involved in NK cell receptor signaling and cytotoxic effector functions. These changes occur in parallel to a repression of genes involved in TCR signaling and TCR-dependent functions, such as proliferation. Collectively, these observations point to a specific program of CD8 T cell differentiation, whereby cells acquire innate-like characteristics as means of maintaining effector functions despite TCR suppression. The mechanisms underlying the acquisition of such unconventional functions, mediated independently of the TCR were investigated revealing a crucial role for the stimulatory NK cell receptor NKG2D in the regulation of innate-like functions mediated by CD8+ T cells. Overall, the results presented in this thesis contribute to a deeper understanding of the mechanisms underlying the recognition and elimination of senescent cells by the immune system. Moreover by studying the effects of terminal differentiation in the immune system capacity to fight against abnormal cells, the research here developed represent one step forward towards an integrative approach to studying aging.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Senescence surveillance: the interplay between the immune system and senescent cells
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10066839
Downloads since deposit
93Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item