Abstract
Simple SummaryPost-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications. The clinical and pathological spectrum of PTLD is broad; however, most cases of PTLD are associated with Epstein–Barr virus (EBV) infection and the use of immunosuppression treatment required to prevent graft rejection. While T-cell impairment is known to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of natural killer (NK) cells remains more elusive. NK cells are key elements of the innate immune system that use a sophisticated array of activating, costimulatory, and inhibitory receptors to kill virally infected and/or cancerous cells. In this review we highlight the role of NK cells in the pathogenesis of PTLD, and also identify future avenues for NK cell therapy research. Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein–Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders.
Highlights
This article is an open access articleNatural killer (NK) cells were identified more than four decades ago as innate lymphocytes with the ability to lyse tumor cells without the need for prior sensitization [1,2].natural killer (NK) cells are mounted with a panoply of activating and inhibitory receptors on their surface, suggesting that different NK cell subsets can be identified based on the assortment of NK receptors that are expressed
The T cell immunoglobulin and mucin domain-containing-3 (Tim-3) immune checkpoint is an inhibitory receptor normally expressed by mature NK cells [65], but its expression is generally increased in various types of cancer [66,67,68,69,70]
While an increase in NK cell activity against malignant cells was seen with this method, limited success was observed in patients treated with cytokines such as IL-2
Summary
Natural killer (NK) cells were identified more than four decades ago as innate lymphocytes with the ability to lyse tumor cells without the need for prior sensitization [1,2]. NK cells produce large amounts of chemokines and cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), which play major roles in tuning and controlling adaptive immune responses [4]. Due to their intrinsic capacities, NK cells play important roles in protection against viruses and tumor growth [5,6]. It was reported that peptides derived from EBV latent proteins can impair the recognition of the inhibitory NKG2A receptor, despite being presented by HLA-E, resulting in activation of differentiated, cytotoxic NK cells for the immune control of EBV [16,17]. Diagnosis relies on pathologic examination, immunohistochemistry, peripheral blood immunophenotyping and, when necessary, T-cell receptor (TCR) sequencing showing the germline configuration
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