TGFβ Programs Central Memory Differentiation in Ex Vivo-Stimulated Human T Cells

The adoptive transfer of ex vivo-expanded T cells is a promising approach to treat several malignancies. Several lines of evidence support that the infusion of T cells with early memory features, capable of expanding and persisting after transfer, are associated with better outcomes. We report herein that exposure to exogenous TGF beta during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGF beta suppressed the expression of BLIMP-1, a key orchestrator of effector T-cell differentiation, and led to the upregulation of the memory-associated transcription factor ID3. Accordingly, this was associated with an early memory transcriptional signature in both CD4(+) and CD8(+) T-cell subsets. The T cells stimulated in the presence of TGF beta expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of ex vivo-stimulated T cells into immunodeficient mice confirmed that TGF beta-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versushost disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor-expressing T cells generated in the presence of exogenous TGF beta were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGF beta in memory T-cell differentiation and indicates that TGF beta signaling may be harnessed to program Tcm differentiation in the context of ex vivo T-cell stimulation for adoptive immunotherapy in humans.