Research Highlights

Host-Microbe Multiomic Profiling Identifies Distinct COVID-19 Immune Dysregulation in Solid Organ Transplant Recipients Pickering H, Schaenman J, Phan HV, et al. Nat Commun. 2025;16:586 Despite being immunocompromised because of chronic immunosuppression, solid organ transplant (SOT) recipients do not experience worse COVID-19 mortality compared with nontransplant recipients.1 This observation suggests that their immune responses to COVID-19, despite baseline immunosuppression, are complex, potentially influencing both disease susceptibility and protective mechanisms. However, the characterization of these immune responses remains limited. In their study, Pickering et al2 conducted a case-control analysis of 86 vaccine-naive SOT recipients and 172 vaccine-naive age- and sex-matched controls hospitalized for COVID-19 at 20 sites across the United States. Plasma, serum, peripheral blood mononuclear cells, and nasal swabs were serially collected at several time points from the index hospitalization. Using the established COVID-19 outcome trajectory groups 1–5,3 the authors examined correlations between these groups and immunological parameters. SOT recipients were found to have significantly higher SARS-CoV-2 viral loads at presentation, along with impaired viral clearance compared with non-SOT controls. Mass cytometry of peripheral blood mononuclear cells revealed that plasmablasts and transitional B cells were notably less abundant in SOT recipients at presentation, as was the anti-SARS-CoV-2 spike IgG level. Interestingly, proximity extension assays of serum showed that several cytokines and chemokines were significantly higher in SOT recipients (including C-X3-C motif chemokine ligand 1, interleukin-15 receptor subunit alpha, and KIT ligand), whereas others were lower (including interferon gamma, oncostatin M, tumor necrosis factor superfamily member 14, and chemokine C-C ligand 4). Consistent with these findings, gene set enrichment analysis of PBMC transcriptomics demonstrated increased expression of innate immunity pathways related to complement activation, type I interferon signaling, and interleukin (IL)-1 signaling in SOT recipients; importantly, these pathways remained upregulated over time in SOT recipients but decreased in non-SOT controls. Similarly, gene set enrichment analysis of longitudinal nasal swab transcriptomics showed increased expression of genes related to type I interferon and IL-1 signaling (among other pathways) in the upper respiratory tract of SOT recipients on hospital admission, mirroring the findings in blood. Notably, most of these observations were independent of SARS-CoV-2 viral load, suggesting virus-independent factors may drive the enhanced systemic proinflammatory signaling seen in SOT recipients. Additionally, these findings did not differ between SOT recipients taking tacrolimus and those receiving mycophenolate. The authors also evaluated immune correlates of disease severity in SOT and non-SOT individuals. In SOT recipients, disease severity was associated with significantly reduced CD8+ central memory T cells, CD11c+CXCR5– B cells, and CD56hiCD16lo natural killer cells, as well as a lower expression of genes related to T-cell receptor signaling, CD28 signaling, and phosphorylation of the CD3 and T-cell receptor ζ chains. In contrast, these features were not observed in non-SOT controls. Disease severity in SOT recipients was also linked to reduced expression of genes related to toll-like receptor signaling in the upper airways. However, there was only a weak association with increased serum proinflammatory cytokines compared with controls. This study is the first to use a multiomics approach to examine a broad range of immune parameters in SOT recipients hospitalized with COVID-19. It has several key clinical implications. First, the relatively weak correlation between serum cytokines and disease severity implies that immunomodulatory therapies, such as IL-6 inhibitors or janus kinase inhibitors, may not confer the same benefit in SOT recipients as in the general population. Second, the lack of an association between tacrolimus versus mycophenolate use and disease severity suggests that the common practice of discontinuing tacrolimus over mycophenolate on COVID-19 hospitalization may not be supported by the existing data. Overall, these findings highlight that immune biomarkers predicting COVID-19 severity in SOT recipients could differ significantly from those in the general population, underscoring the need for mechanistic, data-driven interventions to improve outcomes in this vulnerable group. Compassionate Access to Virus-specific T Cells for Adoptive Immunotherapy Over 15 y Neller MA, Ambalathingal GR, Hamad N, et al. Nat Commun. 2024;15:10339. Viral infection is a leading cause of posttransplant morbidity, causing both specific viral syndromes and allograft dysfunction.1 However, posttransplant viral infections often lack targeted therapeutic options other than reducing immunosuppression and may be resistant to antiviral therapy. Adoptive cellular therapy was introduced in the early 1990s as a potential treatment for cytomegalovirus (CMV) infection following allogeneic hematopoietic stem cell transplantation,2 and it has since been expanded to target other pathogens, including Epstein-Barr virus (EBV), BK virus, John Cunningham virus, and adenovirus. In a recent publication in Nature Communications, Neller et al3 described a 15-y comprehensive case series of patients who were treated with allogeneic virus-specific T cells. T cells were isolated from peripheral blood mononuclear cells isolated from healthy blood donors and stimulated with HLA class I– and class II–restricted viral peptide epitopes, followed by 14–17 d of culture in the presence of interleukin-2. By using epitopes from EBV, CMV, BK virus, john cunningham virus, and adenovirus, multiple virus specificities could be generated. Cells were then screened for alloreactivity by co-culture with single-allele HLA reporter cell lines, ensuring no T-cell responses to alloantigens. A proprietary matching algorithm was used to ensure at least 1–2 shared HLA alleles, allowing recognition of HLA-restricted viral epitopes presented by the recipient. In this way, a bank of allogeneic virus-specific T cells was created and made available “off-the-shelf” for compassionate use in immunosuppressed patients with viral infections. Seventy-eight patients were treated with virus-specific T-cell therapy: 50 were stem cell transplant recipients, 17 were solid organ transplant recipients, and the remaining 11 had varied underlying diseases, including cancers, autoimmune disease, or primary immunodeficiency. Results were similar in the stem cell and solid organ transplant groups, with 35 of 50 patients (70%) and 14 of 17 patients (82%) showing clinical improvement, respectively. However, complete disease remission was achieved in only 5 of 50 patients (10%) and 1 of 17 patients (6%), highlighting the difficulties in establishing persistent viral latency in a chronically immunosuppressed patient population. Importantly, the therapy was well tolerated and safe, with no reported serious adverse events, including no cases of graft-versus-host disease or allograft rejection. These results are consistent with other clinical reports of multivirus-specific T-cell therapies in CMV or EBV reactivation posttransplantation.4 Notably, patients eligible for clinical trials and the current case series had advanced or refractory disease, and there were no high-quality control data for comparison. Despite the study design limitations that prevented patient randomization, the authors noted that the greatest efficacy appeared to be in patients earlier in the disease course. Establishing the appropriate place for adoptive T-cell therapy within virus treatment regimens, therefore, remains challenging. One consideration is that virus-specific T cells remain susceptible to immunosuppressive medications in vivo. A novel strategy to engineer immunosuppression resistance using CRISPR-Cas9 might enhance therapeutic efficacy.5 Ultimately, even in cases where no alternative therapies are available or the infection proves resistant to standard treatment, virus-specific T cells appear both safe and at least moderately effective at inducing a therapeutic response. Future clinical trials will be essential to clarify optimal clinical use scenarios and to investigate potential differences in treatment response across various viruses and underlying conditions.