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

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.

Author summary

Mouse cytomegalovirus (mCMV) infection results in initial systemic viremia that is thereafter controlled by the adaptive immune system. Control is mediated in part by T cells that render the virus undetectable systemically, and latent in specific organs, including the lungs and salivary glands. It remains unclear how latent virus is controlled across tissues given the large pool of systemic mCMV-specific T cells. We explored mCMV control in the adipose tissue, whose cellular constituents are potentially susceptible to infection. We found that mCMV infects the adipose tissue during the acute phase, causing local inflammation and a lifelong mCMV-specific CD8 T cell immune response. The response consisted largely from non-recirculating, tissue-resident T cells. The infected adipose tissue showed signs of metabolic changes, that may potentially predispose the infected host to metabolic dysregulation as evidenced by hyperglycemia. Accumulation and persistence of mCMV specific non-circulating resident CD8 T cells (Trm) in adipose tissue reveal a likely generalized mechanism of mCMV tissue reservoir control by Trm cells and identify the adipose tissue as a persistent mCMV reservoir, with potential implications for metabolic health.