Asymptomatic CMV infections in long‐term renal transplant recipients are associated with the loss of FcRγ from LIR‐1⁺ NK cells

Abstract

While it is established that cytomegalovirus (CMV) disease affects NK-cell profiles, the functional consequences of asymptomatic CMV replication are unclear. Here, we characterize NK cells in clinically stable renal transplant recipients (RTRs; n = 48) >2 years after transplantation. RTRs and age-matched controls (n = 32) were stratified by their CMV serostatus and the presence of measurable CMV DNA. CMV antibody or CMV DNA influenced expression of NKG2C, LIR-1, NKp30, NKp46, and FcRγ, a signaling adaptor molecule, on CD56 dim NK cells. Phenotypic changes ascribed to CMV were clearer in RTRs than in control subjects and affected NK-cell function as assessed by TNF-α and CD107a expression. The most active NK cells were FcRγ -LIR-1 + NKG2Cand displayed high antibody-dependent cell cytotoxicity responses in the presence of immobilized CMV glycoprotein B reactive antibody. However, perforin levels in supernatants from RTRs with active CMV replication were low. Overall we demonstrate that CMV can be reactivated in symptom-free renal transplant recipients, affecting the phenotypic, and functional profiles of NK cells. Continuous exposure to CMV may maintain and expand NK cells that lack FcRγ but express LIR-1.

Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections

“…It is plausible that higher anti‐gB antibody titers may compensate for deficiencies in NK cell function in RTR. In our earlier study, FcRγ − LIR‐1 + NKG2C + NK cells from CMV DNA + RTR displayed the highest ADCC responses, suggesting a link with active CMV replication. Data presented here link ADCC with gB antibody levels rather than CMV DNA, but CMV DNA + RTR in our first cohort had higher levels of gB antibody than those with no detectable CMV DNA …”

“…Our data suggest that loss of FcRγ may be a better indicator of NK cell adaptation to CMV infection than NKG2C. High levels of CMV‐specific antibodies in RTR may reflect episodic subclinical reactivations and therefore a higher burden of CMV, in accordance with the higher frequency of CMV detection in transplant recipients . Hence we use RTR to study the clinical and immunological footprints of CMV.…”

“…This was surprising given evidence for selective expansion of NKG2C + NK cells in CMV Ab+ individuals during healthy aging . However, percentages of NKG2C+ NK cells in CMV seropositive individuals may be affected by the NKG2C gene copy number . Failure to observe an expansion of NKG2C+ NK cells was not due to NKG2C genotype as the frequencies of heterozygotes and homozygotes were similar in all groups (data not shown).…”

“…The high burden of CMV in RTR was demonstrated using CMV DNA as evidence of active viral replication and CMV antibody as a measure of the persistent viral burden. 12,13 NK functions were determined via i) the ability of autologous antibodies and NK cells to mediate ADCC and ii) the ability of NK cells to degranulate and produce cytokines following cross-linking with anti-CD16. Effects of a polymorphism in FCRG3A (encoding CD16) were assessed.…”

Persistence of Activated and Adaptive-Like NK Cells in HIV+ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy

“…Furthermore, HCMV reactivation may in fact be a primary driver of FcRγ − NK cell expansion in HIV infection, but the abovementioned limitations with HCMV antibody levels as indicators of HCMV burden may preclude detection of this relationship. We have previously shown the phenotype of adaptive-like NK cells expanded in response to HCMV infection in renal transplant patients differs from those expanded in HIV infection (31, 43), implying that HIV-related factors may drive expansion of adaptive-like NK cells in addition to the effects of HCMV. The lack of an association between FcRγ − NK cells and immune activation found in this study suggests adaptive-like NK cell expansion is driven by mechanisms distinct from immune cell activation.…”