Biological role of T Memory Stem Cells as a Cellular Reservoir for Graft-versus-Host Disease

Abstract

Abstract T memory stem cells (Tscm) are a subset of antigen-experienced, long-lived, self-renewing and multipotent T cells, which reconstitute immunity following hematopoietic cell transplantation (HCT). Here we investigated the biological role of Tscm in acute Graft-versus-Host Disease (GVHD) using a translational non-human primate model. Tscm cells were tracked longitudinally following autologous or allogeneic HCT under different immunoprophylaxis regimens, resulting either in fulminant Th1-dependent ‘Primary GVHD’, late-onset Th17-driven ‘Breakthrough GVHD’, or GVHD-free immune tolerance. Following HCT, Tscm acquired an activated phenotype (Ki67+, CD69+, PD-1+ and CCR5+), but produced low amounts of IFNγ, IL-2, IL-17A, TNFα and Granzyme B. Tscm were a minor population in donor grafts but expanded in peripheral blood (with a reciprocal decline of naïve T cells) early after HCT and then contracted (with a concomitant increase of effector T cells) when recipients developed clinical GVHD. The kinetics of Tscm expansion/contraction correlated closely with clinical disease: Tscm expanded slower and contracted later in animals progressing to Breakthrough compared to Primary GVHD, and Tscm numbers remained stable under tolerizing conditions. At necropsy, animals with GVHD had increased numbers of Tscm in both lymphoid organs (blood, lymph nodes, spleen) and non-lymphoid GVHD-target organs (colon, lungs, liver) compared to GVHD-free animals. Our data demonstrates that Tscm dynamics correlate with GVHD-free survival and suggest that pathogenic T cells infiltrating both lymphoid and non-lymphoid organs transition from the naïve into the effector state via Tscm. Thus Tscm may play a key role as a cellular reservoir for GVHD.