RT Journal Article
SR Electronic
T1 Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 747196
DO 10.1101/747196
A1 Giljun Park
A1 Daehong Kim
A1 Jani Huuhtanen
A1 Sofie Lundgren
A1 Rajiv K. Khajuria
A1 Ana M. Hurtado
A1 Cecilia Muñoz-Calleja
A1 Laura Cardeñoso
A1 Valle Gómez-García de Soria
A1 Tzu Hua Chen-Liang
A1 Samuli Eldfors
A1 Pekka Ellonen
A1 Sari Hannula
A1 Oscar Bruck
A1 Anna Kreutzman
A1 Urpu Salmenniemi
A1 Tapio Lönnberg
A1 Andres Jerez
A1 Maija Itälä-Remes
A1 Mikko A. I. Keränen
A1 Satu Mustjoki
YR 2019
UL http://biorxiv.org/content/early/2019/08/31/747196.abstract
AB Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation. GvHD patients have aberrant T cell expansions, which are thought to drive pathological immune activation. Here we report mechanistic insights that somatic mutations may account for persistent clonal T cell expansions in chronic GvHD (cGvHD). In an index patient suffering from cGVHD, we discovered persisting somatic MTOR, NFKB2, and TLR2 mutations in an expanded CD4+ T clone. In the screening cohort (n=135), the MTOR P2229R kinase domain mutation was detected in two additional cGvHD patients, but not in controls. Functional analysis of the discovered MTOR mutation indicated a gain-of-function alteration in translational regulation yielding in up-regulation of phosphorylated S6K1, S6, and AKT. Paired single-cell RNA and T cell receptor alpha and beta sequencing strongly supported cytotoxicity and abnormal proliferation of the clonally expanded CD4+ T cells. Real-time impedance measurements indicated increased cytotoxicity of mutated CD4 + T cells against the patient’s fibroblasts. High throughput drug-sensitivity testing suggested that mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest a novel explanation for the aberrant, persistent T cell activation in cGvHD, and pave the way for novel targeted therapies.