The T cell immune response to cytomegalovirus across the adult lifecourse

Cytomegalovirus (CMV) is one of the human herpesviruses and infects over 80% of people. Once a person has been infected with CMV the virus can never be cleared from the body and our immune system needs to constantly 'fight' the virus to stop it dividing and causing tissue damage. This balance is quite finely set and CMV is a major problem in patients whose immune system is suppressed, such as those undergoing transplantation. Perhaps because of this 'war of attrition' between the virus and immune system, the T cell immune response that develops against CMV in the blood is the largest that has been recorded against any pathogen. Moreover, studies in populations have shown that this large immune response can be associated with health problems in certain people, such as the elderly or those with kidney disease. In this grant we propose to extend work that we have undertaken over several years to understand exactly how T cells fight CMV and to develop approaches to control the immune response in situations where it becomes a health risk. The work has 4 sections. In the first part we will investigate how the magnitude and composition of the immune response to CMV is established and maintained in people of all ages. We will assess if it is related to the level of virus that people are exposed to when they are first infected and if the level of the 'viral load' that people carry during chronic infection within the blood or liver is also a critical factor. We will also investigate the importance of lymphocytes that kill CMV-infected cells by acting through a molecule called HLA-C. We have shown that these T cells accumulate over the lifetime such that they become extremely common in older people. These cells are highly effective 'killers' of infected cells and, as well as investigating how they develop, we will also assess their potential use for the immunotherapy of CMV infection. In the second part we will exploit the unique features of CMV, and development of powerful technologies, to study fine details of the differentiation of the CD4+ and CD8+ T cell response to CMV. Here we will use HLA-peptide tetramers to isolate virus-specific cells from tissue samples and immediately undertake a detailed assessment of their phenotype using a technology called CyTOF. Moreover, we will determine the transcriptome ('RNA profile') of the cells and also assess their epigenetic status. This will allow us, for the first time, to see how genomic regulation defines how human antigen-specific T cell responses develop. An important comparison will be between the results in younger and older people as there is evidence that the 'stem cell like' potential of these cells decreases during ageing. In addition, we hope that the comprehensive nature of this work will help understanding of the immune response to diseases such as cancer. Part 3 will address how an important family of 'immune checkpoint receptor (ICR)' proteins such as PD-1 operate in CMV infection. These molecules act to 'suppress' T cell function and antibodies that block their activity are very important in cancer therapy. Here we will take advantage of the CMV model to understand the function of the ICR proteins, in both healthy donors and patients on PD-1 blocking therapy. Finally, we are using anti-viral drugs to control CMV when it becomes a danger to health. We have undertaken two such studies in donors and patients and find that this does indeed suppress the level of CMV in the body. In this work we will undertake a detailed analysis of how treatment influenced the immune response to CMV. The aim here is that this will guide the introduction of anti-viral treatment for patient groups where it may be beneficial, such as the elderly. The work represents one of the most comprehensive studies of how our white cells respond to CMV and we are confident that this will contribute to substantially improving health outcomes, both within CMV infection and beyond.