Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia.

Nico A Contreras,Ilija Jeftic,Katarzyna M Sitnik,Janko Nikolich-Žugich,Christopher Patrick Coplen,Luka Čičin-Šain,Christopher M Snyder

doi:10.1371/journal.ppat.1007890

Abstract

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world’s population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.

Highlights

Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus that infects most of the worldwide population, with largest prevalence being observed in older adults [1,2,3,4]
Mouse cytomegalovirus infection results in initial systemic viremia that is thereafter controlled by the adaptive immune system
Acute CMV infection is characterized by system-wide viremia after which latency and lifelong persistence is established in select cells such as CD34+ monocytes and hematopoietic progenitor cells in humans [5,6,7]

Summary

Introduction

Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus that infects most of the worldwide population, with largest prevalence being observed in older adults [1,2,3,4]. In the course of lifelong infection, cycles of latency and reactivation drive an expansion of CD8 T cells, termed memory inflation (MI), that in some cases reaches up to 30–50% of the total memory compartment in mice and men [15,16]. The magnitude of this memory response is largely unparalleled in any other infection and for this reason CMV has been used as a model to understand the effects of MI during immune aging [3,17,18,19,20]

Methods

Results

Conclusion