As a hematologist and physician-scientist who specializes in bone marrow transplantation, Dr. Albert Yeh describes the “holy grail” of transplantation biology that has yet to be answered: “how do you separate graft-versus-host and graft-versus-leukemia?” Graft-versus-host-disease (GVHD) remains a serious, sometimes fatal, complication that can occur from hematopoietic stem cell transplantation which is often used as a treatment for blood cancers. GVHD occurs when donor T cells recognize certain cell surface proteins, belonging to the major histocompatibility complex (MHC), on normal host cells as foreign and starts attacking them. Dr. Yeh reasons that “if you could separate anti-leukemia and anti-host T cell clones, by mapping what the T cells react to,” you could help answer this question. He recalls, “one of my mentors once told me to work on an ‘unsolvable question’,” so that there would always be more research to do. Figuring out how to distinguish graft-versus-host and graft-versus-leukemia response and prevent GVHD is his ‘unsolvable question’. Despite decades of research, Yeh explains that “it still seems pretty random which T cell clones will expand and difficult to predict.”
Conducting research in Dr. Geoffrey Hill’s lab, part of the Translational Science and Therapeutics Division at Fred Hutch, Dr. Yeh utilized established mouse model transplant systems to study the expansion rates of donor T cells to determine if T cell expansion is predictable on a clonal level. The decades old paradigm maintained that the primary determinant of GVHD is dependent on the genetic relationship between the donor and host. When a donor T cell recognizes host cells as foreign due to mismatches in MHC antigens, this sets off an alarm and calls for that T cell to expand and attack what it has perceived as a threat. If the host cell recognized is cancerous, graft-versus-leukemia effect helps eliminate the cancer, but when normal cells are recognized as foreign, T cells attack the transplant recipient’s healthy cells leading to complications. However, in a recently published Immunity study, Dr. Yeh and researchers from Fred Hutch found that the genetic relationship between the donor and host did not fully explain which T cells expand and that a significant contributor was the host’s gut microbiome. Yeh admits that he hadn’t intended to journey down the microbiome path, so “it was surprising that it took this turn and showed how the whole idea of transplant donor-host genetics isn’t the whole story.”
Before the story veered towards the microbiome, the researchers used matched, genetically identical donor and recipient mouse models, alongside mismatched ones in comparison, and performed hematopoietic stem cell transplantation. In both matched and mismatched models, the authors observed a small fraction of selective T cell expansion, suggesting that MHC-independent factors were influencing clonal expansion since this similarly occurred in the genetically identical matched pairs. Knowing that the gut microbiota has been shown to influence the presence and severity of GVHD, the research team asked if the microbiome might do so through dictating T cell expansion. Treatment with antibiotics at the time of transplantation to eliminate the microbiome indeed diminished the fraction of selective T cell expanders! Yeh comments that this suggested that “bacteria may be causing inflammation and making GVHD worse.”
To address the possibility that the microbiota-dependent T cell expansion occurred via increased inflammation, Yeh also treated mice with low or high doses of total body irradiation, which increases systemic inflammation. In contrast to the antibiotic treated mice, irradiation and subsequent inflammation had no effect on selective T cell expansion, indicating that the microbiome does not influence clonal expansion via increasing inflammation. Yeh was surprised by this result, stating “changing inflammation itself doesn’t seem to matter, but if you change the levels of microbes, it changes how T cells expand. We then took advantage of mouse strains from different vendors, which have different microbiomes,” and through this approach him and the research team demonstrated that microbiota-specific donor T cells increase the severity of GVHD particularly in the presence of a cognate antigen, or one that a T cell already has a receptor for and is primed to recognize. Additionally, their work demonstrated that the pathogenicity of this microbiota-specific T cell population was enhanced by the presence of an allogeneic T cell response through tumor necrosis factor (TNF) signaling, where TNF is a known factor that can worsen GVHD. These findings contrast with the current dogma that GVHD is driven by donor-host mismatches in histocompatibility antigens and this data supports that the “microbes themselves are presented as minor antigen and are really an extension of the host’s genetics,” explains Yeh.
As a physician-scientist, Dr. Yeh ultimately hopes that this work will translate back to the clinic and mitigate GVHD or its severity and improve transplant outcomes. Working with patients he describes as “a bit of a reality check, you can see that GVHD is a really big problem” that needs a solution. One of the ways he is pushing this project towards creating clinical applications, is by translating some of this work into humans by looking at T cell clones and the microbiome in patient samples. To which he expresses his gratitude towards the patients willing to donate tissues, sharing that “these patients know that this won’t directly help them, but that it might help others in the future.” Breaking down and simplifying how to translate this work to the clinic, Yeh reasons that you could “either change the T cell composition, perhaps skewing it towards a regulatory phenotype, or change the microbiome composition, to change the outcome of GVHD.” Alongside translating these findings made in mice to analyzing human samples, Yeh is continuing to work with mouse models to piece out some of the big questions this study raised including understanding how these T cell clones persist overtime and behave differently in various tissues.
This work “changes what we classically thought of as the transplant paradigm,” that GVHD is dictated by genetic differences between donor and transplant recipient, but now we know that “this extends into the microbiome and that the microbiome affects transplant outcomes,” Dr. Yeh shared. Through understanding more about the mechanisms underlying donor T cell and host microbiome interactions, this work will hopefully fuel new therapies that will prevent or lessen the burden of GVHD and improve transplant outcomes in patients. Dr. Yeh concluded by acknowledging that this important work would not be possible without the support of his mentor Dr. Geoff Hill whose lab performed the mouse work for this study and Dr. Phil Bradley who was instrumental in modeling T cell expansion.
This work was supported by the National Institutes of Health, the American Society for Transplantation and Cellular Therapy, and the American Society of Hematology.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Geoffrey Hill, Phillip Bradley, Marie Bleakley, Kate Markey and Scott Furlan contributed to this work.
Yeh AC, Koyama M, Waltner OG, Minnie SA, Boiko JR, Shabaneh TB, Takahashi S, Zhang P, Ensbey KS, Schmidt CR, Legg SRW, Sekiguchi T, Nelson E, Bhise SS, Stevens AR, Goodpaster T, Chakka S, Furlan SN, Markey KA, Bleakley ME, Elson CO, Bradley PH, Hill GR. 2024. Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation. Immunity.