Macaulay, R.; (2011) The role of immune inhibitory receptors in age-associated immune decline. Doctoral thesis , UCL (University College London).

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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 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.

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