Unlike immunocompetent healthy subjects who carry EBV infection in a latent form, approximately 70% of EBV asymptomatic immunosuppressed pediatric heart transplant (HTx) recipients carry chronic EBV loads in peripheral blood, placing them at higher risk of late-onset PTLD. These increased EBV loads in peripheral blood may be due to impaired EBV-specific CD8⁺T cell surveillance and increased EBV reactivation. Chemokines and their receptors are known to play important roles in the immune surveillance and pathogenesis of viral infections, by controlling activated/memory CD8⁺T lymphocytes migration at inflammatory sites of antigenic challenge. Here we investigated for the first time the expression pattern of Th1-specific chemokine receptors CXCR3 and CCR5, and of T follicular cell–specific chemokine receptor CXCR5 on circulating CD8⁺T lymphocytes from pediatric HTx who carry low viral loads (LVL; n=10) or high viral loads (HVL; n=3) as compared to healthy controls (HC; n=10). Our results show that both pediatric HTx patients groups and HC co-express comparable levels of CXCR3/CCR5 (LVL=27% ± 19%, HVL=17% ± 9%, HC=25% ± 16%) and minimal levels of CXCR5 (3% ± 2.2%; 6% ± 9% and 3% ± 2%) on their circulating CD8⁺T cells. Conversely, EBV-specific memory CD8⁺T cells from pediatric HTx patients display overall decreased levels of CXCR3/CCR5, with HVL carriers presenting the lowest expression as compared to HC (45% ± 24%; 27% ± 28%, and 53% ± 15%), suggesting their potential impaired ability to migrate into inflammatory tissues. Interestingly, four out of ten LVL pediatric HTx patients showed significant up-regulation of CXCR5 on their peripheral blood EBV-specific CD8⁺T cells. These cells also co-expressed CXCR3 and ICOS, indicating their activated status and unique migratory properties that may allow them to migrate into B cell follicles of the tonsils (where EBV-reactivation may occur) and cross-talk to B lymphocytes. Monitoring the timing of expression and patterns of the chemokine receptors on EBV-specific CD8⁺T cells from pediatric HTx patients that carry chronic EBV loads may be critically important for the understanding of EBV-specific immune control and risk of complications in this setting.

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