Trends in Immunology
ReviewMemory T cell inflation: understanding cause and effect
Section snippets
Memory T cell inflation and cytomegalovirus infection
The Herpesviridae are a large family of DNA viruses characterized by their ability to produce persistent infections. Human cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus and 60–80% of people in the developed world display evidence of infection by the age of 80 years [1]. HCMV infection in individuals with a healthy immune system is predominantly asymptomatic but on occasion can cause a mononucleosis-like disease similar to that caused by the γ-herpesvirus Epstein-Barr virus. In neonates
Characteristics of memory T cell inflation
Infection of C57BL/6 mice with MCMV produces a CD8+ T cell response to at least 24 epitopes derived from 18 viral proteins in the acute phase of infection; however, 50 days post infection. When viral latency has developed, the immune response is dominated by five singular epitopes that elicit inflationary responses [including two epitopes derived from the immediate early (IE) gene products] [7]. The MCMV-specific CD8+ T cell responses that dominate during the acute phase are typified by
Antigenic stimulation: antigen, tissues and cells
The underlying mechanisms of memory T cell inflation are beginning to be understood (Figure 2). One factor driving this phenomenon must relate to repetitive antigen exposure 17, 18. Support for the hypothesis that antigen persistence and re-exposure are required for memory T cell inflation comes from a series of observations and experiments. Firstly, inflationary memory T cells have phenotypically signs of activation such as low expression of CD62L, CD127, CD27 and CD28 6, 8. Moreover, adoptive
Importance and therapeutic exploitation of memory T cell inflation
The development of CMV-related disease in the immunocompromised, such as post-transplant and AIDS patients, indicates that T cells are important in controlling CMV [49]. Severe disease can develop in immunologically immature children after congenital infection or after infection of premature infants [50]. The specific importance of T cells is underlined by the successful usage of adoptive immunotherapy, whereby donor T cells are stimulated in vitro using viral lysate or CMV-specific peptides
Potential downsides of memory T cell inflation
In contrast to the potential utility of a CMV-driven immune response in vaccinology is the consideration that CMV may be deleterious to health. CMV is recognized to be associated with several vascular diseases, including atherosclerosis, restenosis, transplant vascular sclerosis (TVS) and chronic rejection of solid organ transplants [59]. Recently, the Sacramento Area Latino Study on Aging showed that individuals with CMV IgG antibody titers in the highest quartile compared with lower quartiles
Concluding remarks
Memory T cell inflation has emerged over the past few years as a prominent feature of CMV immunobiology. Like the definition of immune exhaustion that was observed initially in the LCMV mouse model and has now proven its importance for active chronic viral infections in humans, memory inflation could have important implications well beyond CMV persistence. In particular, exploiting the influence of the inflated populations to protect against infection and possibly cancer is an exciting
Acknowledgements
R.A. received financial support from a Marie Curie Fellowship. PK and GO’H are supported by the Wellcome Trust. We thank CJW for help with illustrations.
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