Djaoud et al. show that Epstein–Barr virus infection triggers two types of human innate immune response, one mediated by the combination of NK cells and γδ T cells and the other committed to a strong NK cell response with little involvement of γδ T cells.
Natural Killer (NK) cells constitute the first line of defense against pathogens and transformed cells. NK cells mature in secondary lymphoid organs including tonsils, where common pathogens like the Epstein-Barr virus (EBV) enter the host and potentially imprint differentiating cells, which then patrol the body via the blood stream. We therefore set out to characterize a distinct human NK cell population in tonsils, which produces high amounts of the immunomodulatory and anti-viral cytokine IFN-γ. We found that (i) the tonsilar IFN-γhigh NK cell subset is CD56brightNKG2A+CD94+CD54+CD62L−; (ii) is present in tonsils ex vivo and is more mature than other CD56bright NK cells in tonsils and less mature than other NK cells in blood; (iii) shows very low plasticity even after prolonged cytokine stimulation; (iv) accumulates in tonsils of EBV-carriers and (v) is able to potently restrict EBV-induced transformation of B cells. Thus, we characterized a distinct and stable IFN-γhigh NK cell subpopulation that can specifically restrict malignant transformation of EBV-infected B cells. This subset should be exploited for future development of cell-based therapeutic approaches in EBV-associated malignancies.
Epstein Barr virus (EBV) is one of the most ubiquitous human pathogens in the world, persistently infecting more than 90% of the adult human population. It drives some of the strongest human CD8 + T cell responses, which can be observed during symptomatic primary infection known as infectious mononucleosis (IM). Despite high viral loads and prolonged CD8 + T cell stimulation during IM, EBV enters latency and is under lifelong immune control in most individuals that experience this disease. We investigated whether changes in T cell function, as frequently characterized by PD-1 up-regulation, occur during IM due to the prolonged exposure to high antigen levels. We readily detected the expansion of PD-1 positive CD8 + T cells together with high frequencies of Tim-3, 2B4, and KLRG1 expression during IM and in mice with reconstituted human immune system components (huNSG mice) that had been infected with a high dose of EBV. These PD-1 positive CD8 + T cells, however, retained proliferation, cytokine production, and cytotoxic abilities. Multiple subsets of CD8 + T cells expanded during EBV infection, including PD-1 + Tim-3 + KLRG1 + cells that express CXCR5 and TCF-1 germinal center homing and memory markers, and may also contain BATF3. Moreover, blocking the PD-1 axis compromised EBV specific immune control and resulted in virus-associated lymphomagenesis. Finally, PD-1 + , Tim-3 + , and KLRG1 + CD8 + T cell expansion coincided with declining viral loads during low dose EBV infection. These findings suggest that EBV infection primes PD-1 positive CD8 + T cell populations that rely on this receptor axis for the efficient immune control of this ubiquitous human tumor virus.
EBV persists life-long in >95% of the human adult population. Whereas it is perfectly immune-controlled in most infected individuals, a minority develops EBV-associated diseases, primarily malignancies of B cell and epithelial cell origin. In recent years, it has become apparent that the course of primary infection determines part of the risk to develop EBV-associated diseases. Particularly, the primary symptomatic EBV infection or IM, which is caused by exaggerated T cell responses, resulting in EBV-induced lymphocytosis, predisposes for EBV-associated diseases. The role of innate immunity in the development of IM remains unknown. Therefore, it is important to understand how the innate immune response to this virus differs between symptomatic and asymptomatic primary EBV infection. Furthermore, the efficiency of innate immune compartments might determine the outcome of primary infection and could explain why some individuals are susceptible to IM. We will discuss these aspects in this review with a focus on intrinsic immunity in EBV-infected B cells, as well as innate immune responses by DCs and NK cells, which constitute promising immune compartments for the understanding of early immune control against EBV and potential targets for EBV-specific immunotherapies.
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