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Abstract
Acute graft-versus-host disease (aGVHD) can occur after hematopoietic cell transplant in patients undergoing treatment for hematological malignancies or inborn errors. Although CD4+ T helper (Th) cells play a major role in aGVHD, the mechanisms by which they contribute, particularly within the intestines, have remained elusive. We have identified a potentially novel subset of Th cells that accumulated in the intestines and produced the serine protease granzyme A (GrA). GrA+ Th cells were distinct from other Th lineages and exhibited a noncytolytic phenotype. In vitro, GrA+ Th cells differentiated in the presence of IL-4, IL-6, and IL-21 and were transcriptionally unique from cells cultured with either IL-4 or the IL-6/IL-21 combination alone. In vivo, both STAT3 and STAT6 were required for GrA+ Th cell differentiation and played roles in maintenance of the lineage identity. Importantly, GrA+ Th cells promoted aGVHD-associated morbidity and mortality and contributed to crypt destruction within intestines but were not required for the beneficial graft-versus-leukemia effect. Our data indicate that GrA+ Th cells represent a distinct Th subset and are critical mediators of aGVHD.
Highlights
Acute graft-versus-host disease is a deleterious alloimmune-mediated response that occurs in patients undergoing hematopoietic cell transplant (HCT) for treatment of hematopoietic malignancies or inborn errors
We observed a population of granzyme A (GrA)+CD8+ T cells in all organs examined in allogeneic recipients that was present in lower percentages in syngeneic recipients (Figure 1, B and C)
To determine if GrA+ T helper (Th) cells were related to IFN-γ–producing Th1 cells, we analyzed lineage-specific cytokine and transcription factor expression (Supplemental Table 2; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.124465DS1) within intestinal CD3+CD4+ T cells using time-of-flight cytometry (CyTOF)
Summary
Acute graft-versus-host disease (aGVHD) is a deleterious alloimmune-mediated response that occurs in patients undergoing hematopoietic cell transplant (HCT) for treatment of hematopoietic malignancies or inborn errors. CD4+ T helper (Th) cells within the donor graft that recognize allogeneic HLA molecules are major effectors in aGVHD. Intestinal aGVHD has been described as largely a Th1-mediated response [3,4,5]. The role of IFN-γ in aGVHD remains highly controversial. Neither donor- nor host-derived IFN-γ was required for aGVHD [6,7,8]. IFN-γ played a protective role in aGVHD [9, 10], suggesting that other Th lineages may promote disease
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