Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease

Abstract

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4 + T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4 + T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.

Granzyme-Producing CD4 T Cells in Cancer and Autoimmune Disease

“…This is significant as these basal crypt cells have previous been reported to express MHCII (52) and may be a direct target of GrA-producing cells. GrAexpressing CD4 T cells were also recently identified at high levels in the peripheral blood of a chronic GVHD patient (53), stressing the potential importance of these cells in driving human disease.…”

Somatic <I>STAT3</I> mutations in CD8⁺ T cells of healthy blood donors carrying human T-cell leukemia virus type 2

“…In addition, higher level of the cytotoxic marker perforin was noted in CD8+ T cells of STAT3 mutated, HTLV-2 positive individuals (Supplementary Figure S1B-C). TCRβ deep sequencing 9 of sorted CD8+ T cells revealed higher clonality index in the STAT3 mutated compared to STAT3 unmuted individuals (Figure 1D). The VAF of the STAT3 Y640F mutation was consistent with clonal event in the largest TCRBV03-01 clone; the other three STAT3 mutations with smaller VAFs likely occurred as subclonal events or in the smaller CD8+ T cell clones (Figure 1E).…”