Functional and phenotypical aspects of murine natural killer cells in the context of education

Neha Patil

    Research output: Types of ThesisDoctoral Thesis


    The field of Natural Killer cell biology has expanded immensely over the last several decades. These cells form a major class of lymphocytes and are an important part of the host immune system. Their role against viral infections and in cancer has widely been studied. Increasing body of work in the field of bacterial defence has brought forth the contribution of NK cells. Our work in this thesis highlights this.
    In the introduction (Chapter 1), we go over the basic biology of NK cells. We aim to understand the different components of the innate immune system, to which NK cells belong. NK cells of humans and mice differ right from their places of origin and development, and in how they differentiate into mature NK cells. We go over the surface markers distinguishing them and how to identify them. NK cell education is a process by which these cells obtain their functionality and how they identify self from non-self. The chapter describes the various models by which the status of education is achieved, and what happens in case of missing self-recognition. After briefly introducing their role in cancer immunosurveillance and in viral infections, we focus on their role in bacterial infections. Experiments demonstrate that NK cells interact directly with the bacteria and indirectly, by cytokines. NK cell functionality differs on depending on their location, and thus when talking about respiratory infections like COPD, we focus on the NK cells in the upper airways and the lungs. NK cells act as a double-edged sword, and it is important to take that into consideration when planning immunotherapies, especially cancer immunotherapies with them. Our review in the same chapter outlines the instances where NK cells have deleterious consequences, for example in autoimmunity or their contribution to a cytokine storm in infections, as well as in transplant biology. Several immune cells interact with NK cells, forming an immune microenvironment. One such being the mucosal associated invariant T cells, described in the last section of the chapter.
    Functional NK cells, by virtue of the education achieved by interaction between their major histocompatibility complex class I molecules and self-specific inhibitory receptors, are able to target various infections. In our first paper (Chapter 2), we performed various experiments to understand the imprint of this education in four strains of mice: B6 wildtype, TAP1-KO, B6CAST and MR1-KO. We emphasize on the functional aspects of the NK cells and built their phenotypical profile at baseline. We take a look at the inhibitory receptors Ly49C/I and NKG2A, in presence of a combination of cytokines interleukin-2, interleukin- 12, interleukin-15 and interleukin-18 and observe the changes in the effector potential. We eported a loss in the expression levels of Ly49C/I upon prolonged cultures and changes in the corresponding NK cell cytotoxicity towards target cells.
    Chapter 3 documents our efforts to establish a mouse model of chronic lung infection. Mouse models are used in the study of various diseases, in our case specifically, to study the role of NK cells in lung bacterial infections. We wanted to replicate the disease pathology observed in TAP deficient human patients, where recurrent infections of the respiratory tract are found. Commonly found bacteria include Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Klebsiella, Escherichia coli, Pseudomonas aeruginosa. While acute models of infections have been described in literature, the mentions of chronic infection models are far and few. We attempted to establish a P. aeruginosa chronic infection and wildtype and KO mice, by combining methods used by different groups.
    Microscopy has found its rightful place in biology, right from its first recognised use in the 17th century. Since then, technological advances have enabled us to image and characterise different components of the immune system, their interactions with various infectious agents, and the consequent immune responses. In chapter 4, we challenge the traditional imaging techniques by using ImageStreamX, an imaging flow cytometer, to analyse the interactions between NK cells and bacteria. ImageStreamX allows for the usage of fluorescence intensity signals to quantitatively and qualitatively assess the interactions, and performs statistical analysis as well. We found that the interaction is dynamic in nature
    Original languageEnglish
    Awarding Institution
    • University of Luxembourg
    • Zimmer, Jacques, Supervisor
    Award date3 Feb 2023
    Publication statusPublished - 3 Feb 2023


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