Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects

Abstract

Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

“…The full size of the response to CMV in humans (represented by 213 protein-spanning peptide pools) can be extrapolated from the responses to 19 proteins, including 6 dominant CD4 and 15 dominant CD8 T cell targets (Sylwester et al 2005). Periodic reactivation of latent CMV is thought to repetitively Btickle^the T cell compartment, gradually increasing its size over time (Holtappels et al 2000;Karrer et al 2003).…”

“…Periodic reactivation of latent CMV is thought to repetitively Btickle^the T cell compartment, gradually increasing its size over time (Holtappels et al 2000;Karrer et al 2003). Indeed, the number of human cytomegalovirus (HCMV)-specific αβ T cells in an otherwise healthy individual has been shown to range from 10 to 40% (Sester et al 2002;Sylwester et al 2005;Klenerman and Oxenius 2016). Homeostatic regulation of the size of lymph nodes and spleen led researchers to believe an upper boundary exists for the total number of memory T cells.…”

Mouse CMV infection delays antibody class switch upon an unrelated virus challenge

“…Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus, characterized by its ability to latently persist in the host (Pass, 2001) and mount extremely powerful immune response (Sylwester et al, 2005). Several reports have shown an association of latent CMV infection and parameters associated with immune aging.…”

Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity

“…Although generally considered an innocent infection in the immunocompetent host, accumulating evidence is now suggesting that this chronic infection may have profound effects on the immune system also in healthy adults. CMV encodes several highly immunogenic antigens and a high proportion of the total CD8 + T cell repertoire is specific for CMV in seropositive donors (Kern et al 1999(Kern et al , 2002Lidehall et al 2005;Sylwester et al 2005). CMV infection increases the lymphocyte count and tilts the composition of the T cell compartment towards a lower frequency of naive T cells and accumulation of memory T cells with a late differentiated phenotype (Chidrawar et al 2009;Derhovanessian et al 2010;Pawelec et al 2009).…”