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The Role of Immune Inhibitory Receptors in Age-Associated Immune Decline

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The Role of Immune Inhibitory Receptors in Age-Associated Immune Decline The role of immune inhibitory receptors in age-associated immune decline Submitted by Richard Macaulay 2011 For the degree of Doctor of Philosophy Department of Immunology and Molecular Pathology, University College London I, Richard Macaulay confirm that the work presented in this thesis is my own. Where information has been derived from other sources I confirm that this has been indicated in the thesis. Signed: 1 Abstract The balance between signals delivered by positive and negative costimulatory molecules is crucial to the ultimate fate of cellular immune responses. Manipulation of T cell costimulatory pathways may offer a novel approach for reinvigorating exhausted T cell responses, especially in the context of chronic infections. T cells also display profound exhaustion in old age and this thesis investigates the hypothesis that T cell inhibitory receptor upregulation may define a reversible defect in age onset immune decline. Data presented here illustrate how T cells utilise different inhibitory receptors as they differentiate and that KLRG1 signalling is causative of dysfunctions in highly differentiated CD8 + T cells. The inhibitory receptors KLRG1 and CTLA-4 are revealed to undergo age-associated upregulations on CD8 + T cells but their blockade does not reverse the characteristic hypo-responsiveness of CD8 + T cells amongst old donors. The dysregulated immune response to lifelong chronic cytomegalovirus (CMV) infection is thought to play a major role in driving age related immune dysfunctions. We found that CMV accelerates age-associated telomere attrition amongst CD8 + and CD4 + T cells. CMV infection is also shown to drive CTLA-4, PD-1 and KLRG1 upregulation on both CD4 + and CD8 + T cells. Moreover, the PD-1/Ligand (L) inhibitory pathway defines a reversible proliferative dysfunction in the responses of CMV specific CD8 + T cells. Specifically, the CD45RA re-expressing memory subset 2 exhibits a proliferative deficiency, relative to their central and effector memory counterparts, that is reversible upon PD-L blockade. However, this augmented proliferative response was not accompanied by increased telomerase function, suggesting this does not result in true reversal of exhaustion. In summary, the dysfunctions of highly differentiated and CMV specific CD8 + T cells can be at least partially reversed by perturbation of inhibitory receptor pathways, whose further manipulation may provide a therapeutic modality to combat age- associated immune decline. 3 Acknowledgements I would like to acknowledge the continual support and encouragement of my supervisors, Doctor Sian Henson and Professor Arne Akbar, without whom this body of work would not have been possible. 4 Publication, Abstract and Poster List Data I have generated has contributed to the following publications, abstracts and posters: - Publications Henson,S.M., Macaulay,R. , Kiani-Alikhan,S. and Akbar,A.N. (2008) The use of the inhibitory receptors for modulating the immune responses. Current Pharmaceutical Design.14(26) , 2643-50. Henson,S.M., Franzese,O., Macaulay,R ., Libri,V., Azevedo,R.I., Kiani-Alikhan,S., Plunkett,F.J., Masters,J.E., Jackson,S., Griffiths,S., Pircher,H.P., Soares,M.V. and Akbar,A.N. (2009). KLRG1 signaling induces defective Akt (Ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood. 113(26), 6619-28. van deBerg,P.J., Griffiths,S.J., Yong,S.L., Macaulay,R ., Bemelman,F.J., Jackson,S., Henson,S.M., ten Berge,I.J., Akbar,A.N. and van Lier,R.A. (2010). Cytomegalovirus infection reduces telomere length of the circulating T cell pool. Journal of Immunology.184 , 3417-3423. Dimitri,D., Azevedo,R.I., Libri,V., Henson,S. M., Macaulay R. , Bagley,D., Kipling,D., Soares,M.V., Battistini,L. and Akbar,A.N. CD45RA Re-Expressing CD4 + 5 Memory T Cells Exhibit p38 MAP kinase Regulated Telomere Independent Senescence (manuscript submitted) Henson,S.M.*, Macaulay,R .*, Griffiths,S.J., Dimitri,D., Azevedo,R.I., Libri,V., Franzese,O., Masters,J.E., Bagley,M.C., Kipling,D., Battistini,L., Freeman,G., Soares,M.V., Akbar,A.N. Multiple signalling events actively maintain senescence pathways in human T cells (manuscript in preparation) *joint first authors Macaulay,R ., Henson,S.M., Akbar,A.N. Ageing, a sife effect of inflammation (manuscript submitted) Abstracts Henson,S.M., Macaulay,R. and Akbar,A.N.. Regulation of CMV-specific CD8+ T cell responses by inhibitory receptor signalling. 2nd CMV & Immunosenescence workshop, 2010, Cambridge Posters Henson,S.M., Macaulay,R. and Akbar,A.N. Senescence is actively maintained by inhibitory receptor signalling. World Immunoregulatory meeting, 2008, Davos 6 Table of Contents List of Figures .............................................................................................................. 14 List of Tables ............................................................................................................... 18 List of Abbreviations ................................................................................................... 19 1 Introduction ........................................................................................................ 22 1.1 How and why we age ...................................................................................... 22 1.1.1 How we age.............................................................................................. 22 1.1.2 Why we age.............................................................................................. 23 1.2 Immunosenescence ......................................................................................... 23 1.2.1 Introduction .............................................................................................. 23 1.2.1.1 The significance of age related immune changes ............................ 24 1.2.1.2 The immune system ......................................................................... 24 1.2.1.3 The ubiquitous nature of immunosenescence .................................. 24 1.2.1.4 Consequences of this age related immune decline .......................... 25 1.2.2 How individual immune system components are affected by ageing...... 26 1.2.3 T cells ....................................................................................................... 27 1.2.3.1 Introduction ...................................................................................... 27 1.2.3.1.1 Activation of Naïve T cells ........................................................ 27 1.2.3.1.2 Effector T cell functions ............................................................. 28 1.2.3.1.3 Memory formation ..................................................................... 29 1.2.3.1.4 Central and effector memory...................................................... 29 1.2.3.1.5 CD45RA-revertant memory T cells ........................................... 30 1.2.3.1.6 Effector and memory subpopulation differentiation pathways .. 31 1.2.3.1.7 Identification of T cell subpopulations ...................................... 32 1.2.3.2 Effects of advancing age on the T cell compartment ....................... 34 1.2.3.2.1 Overview .................................................................................... 34 1.2.3.2.2 CD28 Loss .................................................................................. 35 1.2.3.2.3 Cellular senescence .................................................................... 36 1.2.3.2.3.1 Telomeres ............................................................................ 36 1.2.3.2.3.2 Telomerase .......................................................................... 37 1.2.3.2.3.3 Significance of cellular senescence in immune system ageing .................................................................................. 39 1.2.3.2.4 Inflammaging ............................................................................ 41 1.2.3.2.5 Other age-associated T cell alterations....................................... 43 1.3 What causes these age related T cell changes? ............................................... 44 1.3.1 Thymic Involution ................................................................................... 44 1.3.1.1 Introduction ...................................................................................... 44 1.3.1.2 Age-associated thymic changes ....................................................... 45 1.3.1.3 Homeostatic peripheral expansion ................................................... 45 1.3.1.4 TCR Repertoire Diversity ................................................................ 46 7 1.3.2 Lifelong antigenic burden ........................................................................ 47 1.3.2.1 Persistent poorly controlled antigenic challenges ............................ 48 1.3.2.2 Latent infections............................................................................... 48 1.3.2.3 Other chronic pathogens .................................................................. 50 1.4 CMV ............................................................................................................... 51 1.4.1 Introduction .............................................................................................. 51 1.4.1.1 Background ...................................................................................... 51 1.4.1.2 CMV infection routes and dissemination ........................................ 51 1.4.1.3 Latency ............................................................................................
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