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Abstract
Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.
Highlights
Allogeneic stem cell transplantation remains a highly effective therapy for hematopoietic malignancies that are not curable by chemotherapy and/or radiotherapy
We compared TCRVβ CDR3 clonotypes present at week 2 with those identified from the liver biopsy of a patient who developed acute liver graft versus host disease (GvHD) at 96 days after SCT (Figure 2C, left) and the skin biopsy of a patient who developed acute skin GvHD (Supplemental Figure 2). 94 T cell clones were shared between the week 2 blood and liver acute GvHD (aGvHD) samples (Figure 2C), with the most frequent of these constituting 0.5% of the liver repertoire (Figure 2C, right), increased by 100-fold from a frequency of 0.005% in week 2 blood. These findings indicate that antigen-driven clonal T cells are present by week 2 following allograft and that these may be involved in the development of aGvHD
T cell receptor (TCR) Vβ family analysis demonstrated that autograft T cells retained a polyclonal T cell repertoire during the first 2 weeks of expansion, whereas allograft cells developed an oligoclonal profile by this stage
Summary
Allogeneic stem cell transplantation (allo-SCT) remains a highly effective therapy for hematopoietic malignancies that are not curable by chemotherapy and/or radiotherapy. The potentially curative nature of SCT is due to generation of a graft-versus-leukemia response, which is mediated by the donor immune system. This alloreactive immune response (AIR) can result in graft versus host disease (GvHD), which remains one of the major causes of morbidity and mortality associated with allo-SCT. The initial AIR is mediated by mature T cells transferred within the donor stem cell graft [4], and several studies support the concept that the AIR is generated in the first 2 weeks after transplantation, in line with other primary T cell responses [5,6,7,8,9,10,11]. One of the challenges with the study of AIR in patients following allo-SCT is that transfer of T cells into lymphopenic patients leads to intense homeostatic proliferation, which complicates assessment of the response to antigen-specific allorecognition [19,20,21]
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