A significant proportion of extracellular nucleic acids in plasma circulate highly protected in tumor-specific exosomes, but it is unclear how the release of exosomes is modulated in carcinogenesis. We quantified by cytometry exosomes in plasma of 91 colorectal cancer patients to evaluate their potential as a tumor indicator and their repercussions on diagnosis and prognosis. We examined the involvement of TSAP6, a TP53-regulated gene involved in the regulation of vesicular secretion, in levels of circulating exosomes in plasma of colorectal patients and in HCT116 TP53-(wild-type and null) human colorectal cancer cell lines. The fraction of exosomes in cancer patients was statistically higher than in healthy controls (mean rank ¼ 53.93 vs. 24.35). High levels of exosomes in plasma of patients correlated with high levels of carcino-embryonic antigen (P ¼ 0.029) and with poorly differentiated tumors (P ¼ 0.039) and tended to have shorter overall survival than patients with low levels (P ¼ 0.056). Release of exosomes did not correlate with TSAP6 expression; and regulation of TSAP6 by TP53 was not shown either in tumor samples or in HCT116 cell lines. Although it was not suggested that the TP53/TSAP6 pathway regulates the release of exosomes into the plasma of colorectal cancer patients, the level of circulating exosomes may be used as a tumor indicator, because it correlates with poor prognosis parameters and shorter survival.

CD94/NKG2C and lack of FcεRγ (FcRγ) expression are considered markers of the adaptive NK cell response to human CMV (HCMV) infection. Despite the fact that FcRγ− and NKG2Cbright NK cells share some phenotypic, epigenetic, and functional features, their relationship remains unclear. To address this issue, a systematic analysis of NKG2Cbright and FcRγ expression was carried out in NK cells from a cohort of healthy young adults (n = 81) considering NKG2C copy number, previously related to the magnitude of NKG2C+ NK cell expansion. NKG2Cbright and FcRγ− NK cells coincided in a subgroup of HCMV+ individuals, pointing to a common host–virus interaction pattern. Even though FcRγ loss was often confined to expanded NKG2Cbright NK cells, both markers appeared occasionally dissociated, consistent with the existence of distinct adaptive NK cell subsets. Remarkably, FcRγ loss was mostly accumulated within the NKG2Cbright subset in NKG2C+/+ subjects, whereas NKG2C−FcRγ− NK cell subpopulations were more frequently detected in NKG2C+/del donors and also in NKG2Cdel/del individuals, independently of activating killer Ig–like receptor expression. The distribution of other NK receptors (i.e., killer Ig–like receptor, LILRB1, or CD57) supported a sequential differentiation from NKG2CbrightFcRγ+ to NKG2CbrightFcRγ− NK cells. Noticeably, NKG2Cbright NK cells produced more TNF-α in response to Ab-dependent activation, regardless of their FcRγ levels. Moreover, the TNF-α response of NKG2C−FcRγ− subpopulations was lower than that of concurrent NKG2CbrightFcRγ− NK cells, further supporting that FcRγ levels and enhanced potential for cytokine production are uncoupled. Overall, our data extend the characterization of adaptive NK cell subsets that differentiate in response to HCMV, supporting a relationship between their distribution and NKG2C copy number.

HSV-1 establishes life-long latency that can result in clinical relapses or in asymptomatic virus shedding. Although virtually all adults have been exposed to HSV-1, the clinical course varies remarkably. Genetic host variability could be related to this clinical diversity. In this study, we analyzed the contribution of gene families in chromosomes 1, 6, 12, and 19, which encode key regulators of the innate and adaptive immunity, in a cohort of 302 individuals. Class I and class II alleles of the HLA system, the copy-number variation of NK cell receptor genes (KIR and NKG2C), the combinations of killer cell Ig-like receptor and their HLA ligands, and CD16A and CD32A allotypes of variable affinity for IgG subclasses were all studied. Although no major susceptibility locus for HSV-1 was identified, our results show that the risk of suffering clinical HSV-1 infection is modified by MHC class I allotypes (B*18, C*15, and the group of alleles encoding A19), the high-affinity receptor/ligand pair KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism. Conversely, HLA class II and CD32A polymorphisms and NKG2C deletion did not seem to influence the clinical course of herpetic infection. Collectively, these findings support an important role in host defense against herpetic infection for several polymorphic genes implicated in adaptive immunity and in surveillance of its subversion. They confirm the crucial role of cytotoxic cells (CTL and NK) and the contribution of genetic diversity to the clinical course of HSV-1 infection.

Herpes zoster (HZ) is associated with substantial morbidity. It is caused by reactivation of the latent varicella zoster virus (VZV) following decline in cell-mediated immunity, which is commonly age-related, but also occurs in individuals with immunosuppressive diseases and/ or treatment. Since coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with T cell immune dysfunction and there have been reports of HZ in COVID-19 patients, we have performed a review of available literature on whether COVID-19 could trigger HZ. We identified 27 cases of HZ following COVID-19, which most frequently occurred within 1-2 weeks of COVID-19, and the majority of cases had typical presentation. Atypical presentations of HZ were noted especially in patients with lymphopenia. It has been hypothesized that VZV reactivation occurs as a consequence of T cell dysfunction (including lymphopenia and lymphocyte exhaustion) in COVID-19 patients. Based on current evidence, which is limited to case reports and case series, it is not possible to determine whether COVID-19 increases the risk of HZ. Practitioners should be aware of the possible increased risk of HZ during the pandemic period and consider timely therapeutic and preventive measures against it.

A recently developed anti-KIR2DL5 (CD158f) antibody has demonstrated KIR2DL5 expression on the surface of NK and T lymphocytes, making it the last functional KIR identified in the human genome. KIR2DL5 belongs to an ancestral lineage of KIR with Ig-like domains of the D0-D2 type, of which KIR2DL4, an HLA-G receptor, is the only other human member. Despite KIR2DL4 and KIR2DL5 being encoded by genes with similar domain usage, several KIR2DL5 functions resemble more closely those of KIR recognizing classical HLA class I molecules – surface-expressed KIR2DL5 inhibits NK cells through the SHP-2 phosphatase and displays a clonal distribution on NK and T lymphocytes. No activating homolog of KIR2DL5 has been described in any species. The genetics of KIR2DL5 is complicated by duplication of its gene in an ancestor of modern humans living ∼1.7 million years ago. Both KIR2DL5 paralogs have undergone allelic diversification; the centromeric gene is most often represented by alleles whose expression is silenced epigenetically through DNA methylation, thus providing a natural system to investigate the regulation of KIR transcription. The role of KIR2DL5 in immunity is not completely understood, in spite of different attempts to define its ligand. Here we revisit the most relevant characteristics of KIR2DL5, an NK-cell receptor possessing a unique combination of genetic, structural, and functional features.

The genetic susceptibility to multiple sclerosis (MS) is only partially explained, and it shows geographic variations. We analyse here two series of Spanish patients and healthy controls and show that relapsing MS (R-MS) is associated with a gene deletion affecting the hypothetically soluble leukocyte immunoglobulin (Ig)-like receptor A3 (LILRA3, 19q13.4), in agreement with an earlier finding in German patients. Our study points to a gene-dose-dependent, protective role for LILRA3, the deletion of which synergizes with HLA-DRB1*1501 to increase the risk of R-MS. We also investigated whether the risk of suffering R-MS might be influenced by the genotypic diversity of killer-cell Ig-like receptors (KIRs), located only B400 kb telomeric to LILRA3, and implicated in autoimmunity and defence against viruses. The relationship of LILRA3 deletion with R-MS is not secondary to linkage disequilibrium with a KIR gene, but we cannot exclude some contributions of KIR to the genetic susceptibility to R-MS.

Inhibitory Killer-cell Immunoglobulin-like Receptors (KIR) specific for HLA class I molecules enable human natural killer cells to monitor altered antigen presentation in pathogen-infected and tumor cells. KIR genes display extensive copy-number variation and allelic polymorphism. They organize in a series of variable arrangements, designated KIR haplotypes, which derive from duplications of ancestral genes and sequence diversification through point mutation and unequal crossing-over events. Genomic studies have established the organization of multiple KIR haplotypes-many of them are fixed in most human populations, whereas variants of those have less certain distributions. Whilst KIR-gene diversity of many populations and ethnicities has been explored superficially (frequencies of individual genes and presence/absence profiles), less abundant are in-depth analyses of how such diversity emerges from KIR-haplotype structures. We characterize here the genetic diversity of KIR in a sample of 414 Spanish individuals. Using a parsimonious approach, we manage to explain all 38 observed KIR-gene profiles by homo-or heterozygous combinations of six fixed centromeric and telomeric motifs; of six variant gene arrangements characterized previously by us and others; and of two novel haplotypes never detected before in Caucasoids. Associated to the latter haplotypes, we also identified the novel transcribed KIR2DL5B * 0020202 allele, and a chimeric KIR2DS2/KIR2DL3 gene (designated KIR2DL3 * 033) that challenges current criteria for classification and nomenclature of KIR genes and haplotypes.

Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.