Abstract
Infection with Cytomegalovirus is associated with accelerated immunosenescence. Expansions of CMV-specific T cell responses have previously been demonstrated to affect the ability of T cells to respond to other infections. Most people above 60years of age display M. tuberculosis-specific immunity because of vaccination, exposure, or both. T-cell responses can be assessed by measuring intracellular IFN-γ in vitro after tuberculin stimulation. Here we investigated tuberculin-specific CD4 T-cell responses in independently living healthy older people in the South of England using flow-cytometry. Individuals were investigated for tuberculin and CMV-specific T-cell immunity using in vitro antigen stimulation followed by intracellular staining for IFN-γ, TNF-α, IL2, as well as degranulation and CD154 upregulation. We also examined a control group of younger individuals (20–35years of age). There was no significant difference between older and young people in regards to tuberculin responsiveness of CD4 T-cells; however, older people seemed to show more outliers. Increased responsiveness to tuberculin was significantly correlated to CMV responsiveness but not age. In older donors, the memory phenotype of tuberculin-induced T-cells was significantly skewed towards a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals and the degree of skewing correlated quantitatively with the size of the CMV-specific CD4 T-cell response. This is a fundamental advance over previous reports of changes of the tuberculin-specific CD4 T-cell response with CMV serostatus. Our results show that how the immune system responds to CMV has a fundamental impact on the phenotype and function of the immune response to mycobacterial antigens in older life.
Highlights
Human Cytomegalovirus (HCMV) is the largest known herpes virus and infects up to 90% of the population worldwide
Since the number of naive T cells is central to immune efficacy, CMV infection has been associated with premature T cell response decline and reduced ability of the host to mount effective immune responses against other infections or vaccination
Our results confirm that in older people tuberculin-induced T-cells show a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals; our results significantly extend previous findings to show that it is the actual size of the CMV-specific response rather than its mere presence that affects both phenotype and function of the immune response to mycobacterial antigens in older life
Summary
Human Cytomegalovirus (HCMV) is the largest known herpes virus and infects up to 90% of the population worldwide. CMV establishes latent infections, which are asymptomatic in the immunocompetent host, the impact of CMV on the memory T cell compartment is substantial. CMV infection results in an accumulation of late differentiated T cells and an increased ratio of memory over naive T cells, with approximately 10% of total T cell responses dedicated to CMV antigens. During ageing, both CD4 and CD8 naive T cells significantly decline in seropositive individuals (Chidrawar et al, 2009; Fagnoni et al, 2000; Moro-Garcia et al, 2012). Since the number of naive T cells is central to immune efficacy, CMV infection has been associated with premature T cell response decline (or immunosenescence) and reduced ability of the host to mount effective immune responses against other infections or vaccination
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