CMV drives the expansion of highly functional memory T cells expressing NK‐cell receptors in renal transplant recipients

Abstract

Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post-transplant. We describe how active and latent CMV affect T-cell subsets in RTRs who are stable on maintenance therapy. T-cell responses to CMV were assessed in RTRs (n = 54) >2 years post-transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8 T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T-cell (T ), terminally differentiated T-cell (T ) and CD57 T cell populations. Expression of NK-cell receptors, LIR-1 and KLRG1 on CD4 and CD8 CD57 T and T cells correlated with elevated interferon-γ and cytotoxic responses to anti-CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8 T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) -1 peptides. The data show that latent and active CMV infection can alter T-cell subsets in RTRs many years after transplantation, and up-regulate T-cell expression of NK-cell receptors. This may enhance effector responses of CD4 and CD8 T cells against CMV.

Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells

“…Although T EM cells show generally high cytokine production potential, contrasting findings have been published for T EMRA cells, reporting either high or low cytokine production potential; the latter being attributed to an exhausted state with characteristics of end-stage differentiation, showing acquirement of killer cell lectin-like G1 (KLRG1) and CD57 but loss of CD28 and CD27 expression 9,18–21 . Similar findings suggesting multifunctionality within a subset have also been observed for T EM cells 21,22 . Thus, T EM and T EMRA populations defined by the CD45RA/CCR7 classification seem to represent a pool of cells, which are functionally and phenotypically heterogeneous.…”

HIV patients, healthy aging and transplant recipients can reveal the hidden footprints of CMV

“…Whilst this is not specified in most commercial kits, we find that levels of antibody reactive with a lysate of infected cells rise with age in HIV patients and healthy controls, T-cell responses to CMV antigens may reflect levels of CMV replication (antigen burden), with or without being protective. This fits evidence that responses can be higher in immunosuppressed transplant recipients and HIV patients than in healthy donors [19,20]. Indeed the expansion of CMVreactive T-cells may dominate the phenotypic profile of the T-cell population, as discussed below.…”

Progressive change in expression of killer-like receptorsr and GPR56 expression defines the cytokine production potential of human CD4+ T memory cells

“…Indeed, T EMRA cells have characteristics of end-stage differentiation and thus a very low proliferative potential (19,21,22), they do acquire KLRG1 and CD57 but loose CD28 and CD27 expression (21). However, acquisition of CD57 and loss of CD28 or CD27 expression is not exclusive for T EMRA cells but also observed for some T EM cells (22,23). These results demonstrate, that T EM and T EMRA populations defined by the CD45RA/CCR7classification seem to represent heterogeneous pools of cells which are functionally and phenotypically not clearly defined and distinguishable.…”