Study provides a new paradigm for managing transplant‑related immune complications

Acute graft-versus-host disease (aGVHD) is one of the most serious complications after allogeneic hematopoietic stem cell transplantation (allo‑HSCT). It can rapidly progress to multi‑organ failure, yet current diagnosis still relies largely on clinical symptoms and histological confirmation once tissue damage has already occurred. As a result, clinicians often miss the optimal window for intervention, and the lack of sensitive, specific early biomarkers has long been a major obstacle to effective aGVHD management.

In a study recently published in hLife, Dr. Shunqing Wang and colleagues from the Department of Hematology at Guangzhou First People's Hospital carried out longitudinal immune monitoring in 111 allo‑HSCT recipients for up to 100 days after transplant. By tracking multiple lymphocyte subsets over time, they found that a distinct population of activated CD38⁺HLA‑DR⁺CD8⁺ T cells expanded dramatically in patients who went on to develop aGVHD. When the proportion of these cells in peripheral blood rose above 36.6% within the first month after transplantation, it served as a highly accurate early warning signal for subsequent aGVHD.

To test whether this subset could also guide treatment, the team further analyzed 20 patients with established aGVHD. They observed that in responders who achieved complete or partial remission, the frequency of CD38⁺HLA‑DR⁺CD8⁺ T cells fell markedly as clinical symptoms improved. In contrast, in non‑responders or patients with progressive disease, this population remained persistently elevated despite therapy. These findings suggest that simple, repeated flow‑cytometric measurement of this subset could function as a "real‑time dashboard" to monitor therapeutic efficacy and support timely adjustment of immunosuppressive regimens.

The researchers then asked whether directly eliminating these pathogenic cells might offer a new treatment strategy. Using a mouse model of aGVHD, they administered the anti‑CD38 monoclonal antibody daratumumab, which is already approved for multiple myeloma, to selectively deplete CD38‑expressing CD8⁺ T cells. Daratumumab treatment efficiently cleared the culprit cells, alleviated tissue damage, and significantly improved survival in the animals, highlighting the translational potential of repurposing CD38‑targeted therapy for aGVHD.

Mechanistic experiments revealed that these activated CD8+ T cells do not rely on classical T‑cell receptor (TCR) recognition of alloantigen. Instead, inflammatory cytokine IL‑15 drives "bystander" activation of CD8⁺ T cells via the PI3K/mTOR signaling pathway. Once activated, the cells up‑regulate the activating receptor NKG2D and recognize stress‑induced ligands such as MIC‑α on target tissues, unleashing potent, innate‑like cytotoxicity that contributes to tissue injury. This IL‑15/PI3K/mTOR/NKG2D axis provides a mechanistic explanation for how CD38⁺HLA‑DR⁺CD8⁺ T cells can mediate damage even in the absence of strong TCR stimulation.

Taken together, the study establishes CD38⁺HLA‑DR⁺CD8⁺ T cells as a central hub linking prediction, mechanism, and therapy in aGVHD. A simple percentage cutoff of 36.6% in the first month after transplant can identify patients at high risk before symptoms appear; dynamic tracking of this subset reflects treatment response; and CD38‑targeted depletion offers a promising avenue for precise intervention. By shifting immune surveillance for aGVHD from "after symptoms" to "before symptoms", this work provides a new paradigm for managing transplant‑related immune complications and may inspire similar strategies in other T‑cell‑mediated diseases.