CD8⁺ T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8⁺ T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8⁺ T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8⁺ T cell landscape. Here, we demonstrate that circulating TOX⁺ CD8⁺ T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8⁺ T cells generally expressed TOX, whereas naive and early-differentiated memory CD8⁺ T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8⁺ T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8⁺ T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8⁺ T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8⁺ T cell subsets and not exclusively linked to exhaustion.

Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch ( P <0.001), serological Epstein-Barr virus mismatch recipient−/donor+ ( P <0.001), use of reduced intensity conditioning ( P =0.002), acute graft- versus -host disease grade II to IV ( P =0.006), pre-transplant splenectomy ( P =0.008) and infusion of mesenchymal stromal cells ( P =0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease ( P <0.001). The study identifies patients at risk of post-transplant lymphoproliferative disease after transplantation in need of pre-emptive measures.

Viral infections are major complications after allogeneic hematopoietic stem cell transplantation (HSCT). During posttransplant immunosuppression the regular T-cell control is compromised. Even if treatment strategies against infections caused by herpes viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus have improved, the mortality rate is still considerable. If primary antiviral therapy fails or cannot be tolerated, adoptive therapy with virus-specific cytotoxic T cells (CTL) can be utilized. In this study, we used virus-specific CTLs to treat 8 patients suffering from severe viral infections after allogeneic HSCT. Using positive selection with HLA multimers and magnetic beads, we isolated CTLs from both frozen donor material as well as third-party donors within hours. At 90 days after CTL infusions 7 out of 8 patients were still living. CTLs infused from third-party donors were detected in 5 of 6 patients up to 76 days after infusion. No graft-versus-host disease associated with CTL infusions was observed. Our separation approach offers a rapid alternative for adoptive CTL therapy if primary antiviral treatment strategies fail. Because no prolonged expansion steps are needed, this method may be used for early treatment of patients suffering from life-threatening infectious complications.

γδ T cells are clonotypically distinct in ascites and tumors of patients with ovarian cancer and their functionality correlates with clinical outcome.

Allogeneic hematopoietic stem cell transplantation (HSCT) using αβ T-/B-cell–depleted grafts recently emerged as a transplant strategy and highlighted the potential role of γδ T cells on HSCT outcomes. Our aim was to scrutinize available evidence of γδ T-cell impact on relapse, infections, survival, and acute graft-versus-host disease (aGVHD). We performed a systematic review and meta-analysis of studies assessing γδ T cells in HSCT. We searched PubMed, Web of Science, Scopus, and conference abstracts from inception to March 2019 for relevant studies. We included all studies that assessed γδ T cells associated with HSCT. Data were extracted independently by 2 investigators based on strict selection criteria. A random-effects model was used to pool outcomes across studies. Primary outcome was disease relapse. We also assessed infections, survival, and aGVHD incidence. The review was registered with PROSPERO (CRD42019133344). Our search returned 2412 studies, of which 11 (919 patients) were eligible for meta-analysis. Median follow-up was 30 months (interquartile range, 22-32). High γδ T-cell values after HSCT were associated with less disease relapse (risk ratio [RR], 0.58; 95% confidence interval [95% CI], 0.40-0.84; P = .004; I² = 0%), fewer viral infections (RR, 0.59; 95% CI, 0.43-0.82; P = .002; I² = 0%) and higher overall (HR, 0.28; 95% CI, 0.18-0.44; P < .00001; I² = 0%) and disease-free survivals (HR 0.29; 95% CI, 0.18-0.48; P < .00001; I² = 0%). We found no association between high γδ T-cell values and aGVHD incidence (RR, 0.72; 95% CI, 0.41-1.27; P = .26; I² = 0%). In conclusion, high γδ T cells after HSCT is associated with a favorable clinical outcome but not with aGVHD development, suggesting that γδ T cells have a significant effect on the success of HSCT. This study was registered with PROSPERO as #CRD42019133344.