Natural killer (NK) cells are critical for restricting viral infections and mediating tumor immunosurveillance. Epstein-Barr virus (EBV) and Plasmodium falciparum malaria are known risk factors for endemic Burkitt lymphoma (eBL), the most common childhood cancer in equatorial Africa. To date, the composition and function of NK cells have not been evaluated in eBL etiology or pathogenesis. Therefore, using multiparameter flow cytometry and in vitro killing assays, we compared NK cells from healthy children and children diagnosed with eBL in Kenya. We defined 5 subsets based on CD56 and CD16 expression, including CD56^negCD16^pos. We found that licensed and terminally differentiated perforin-expressing CD56^negCD16^pos NK cells accumulated in eBL children, particularly in those with high EBV loads (45.2%) compared with healthy children without (6.07%) or with (13.5%) malaria exposure (P = .0007 and .002, respectively). This progressive shift in NK cell proportions was concomitant with fewer CD56^dimCD16^pos cells. Despite high MIP-1β expression, CD56^negCD16^pos NK cells had diminished cytotoxicity, with lower expression of activation markers NKp46, NKp30, and CD160 and the absence of TNF-α. Of note, the accumulation of poorly cytotoxic CD56^negCD16^pos NK cells resolved in long-term eBL survivors. Our study demonstrates impaired NK cell–mediated immunosurveillance in eBL patients but with the potential to restore a protective NK cell repertoire after cancer treatment. Characterizing NK cell dysfunction during coinfections with malaria and EBV has important implications for designing immunotherapies to improve outcomes for children diagnosed with eBL. Key Points Terminally differentiated CD56^neg NK cells expand in children after chronic malaria exposure and in those diagnosed with eBL. NK cells in eBL patients express high levels of MIP-1β in lieu of TNF-α, and normal NK cell profiles appear to be restored in eBL survivors. Visual Abstract

Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A⁺ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C⁺ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56^-CD16⁺CD38⁺CXCR6⁺ NK cells. CD56^-CD16⁺ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56^-CD16⁺ NK cell differentiation.

Despite a large body of literature, the impact of chronic cytomegalovirus (CMV) infection in donor on long‐term graft survival remains unclear, and factors modulating the effect of CMV infection on graft survival are presently unknown. In this retrospective study of 1279 kidney transplant patients, we analyzed long‐term graft survival and evolution of CD8⁺ cell population in donors and recipients by CMV serology and antigenemia status. A positive CMV serology in the donor was an independent risk factor for graft loss, especially among CMV‐positive recipients (R⁺). Antigenemia was not a risk factor for graft loss and kidneys from CMV‐positive donors remained associated with poor graft survival among antigenemia‐free recipients. Detrimental impact of donor's CMV seropositivity on graft survival was restricted to patients with full HLA‐I mismatch, suggesting a role of CD8⁺ cells. In R⁺ patients with positive CMV antigenemia during the first year, CD8⁺ cell count did not increase at 2 years posttransplantation, in contrast to R⁻ recipients. In addition, marked CD8⁺‐cell decrease was a risk factor of graft failure in these patients. This study identifies HLA‐I full mismatch and a decrease of CD8⁺ cell count at 2 years as important determinants of CMV‐associated graft loss.

Indirect effects of cytomegalovirus (CMV) in transplantation are of three types: increase in systemic immunosuppression, increased risk of malignancy (especially Epstein-Barr virus-related B-cell lymphoproliferative disease), and the possible contribution to allograft injury. Despite modern and potent antiviral drugs, the real impact of CMV in transplantation, especially kidney transplantation, remains a challenge because many confounding factors arise when analyzing this question.This review will fuel the discussion and review some of the recent data. A recent study on cardiac allograft in mice has shown that CMV in latently infected recipients could break graft acceptance. Although the exact nature of response was not addressed, this study suggested that CMV reactivation inside the graft played an important part in graft losses. Other recent results suggest that the quality of immune response against CMV influences graft outcome in both cardiac and kidney transplant patients. Other evidence suggests the link between CMV infection, immune senescence and vascular disease in the whole population. Studies have opened the perspective for new strategies to prevent indirect effects of CMV. Although a causal relationship between CMV reactivation and graft injury is supported by a large body of experimental and clinical data, definitive proof in clinical transplantation is still lacking to exclude an associative relationship. Large randomized clinical trials analyzing long-term graft survival and comparing prophylaxis with preemptive, especially D/R, is probably an efficient way to establish a causal relationship. Research on new antiviral strategies applicable over the long term is important.

Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4 ⁺ and CD8 ⁺ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8 ^dim T cells with an innate-like profile (Granzyme B ^hi , IFNγ ^low , TNFα ^low , PLFZ ^hi , ID2 ^hi , IKZF2 ^hi ) in contrast to age-matched children residing in a low pathogen–exposure area who display a more conventional CD8 ^bright profile (IFNγ ⁺ , TNFα ⁺ , CCL4 ⁺ ). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8 ^dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses.