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

Amina Dahmani,Jean-Sébastien Delisle,Myriam Khalili,Caroline Lamarche,Valérie Janelle,Manon Richaud,Cédric Carli,Ksenia Bezverbnaya,Mathieu Goupil,Jonathan L Bramson

doi:10.1158/2326-6066.cir-18-0691

Abstract

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 TGFβ during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGFβ 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 TGFβ expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of ex vivo-stimulated T cells into immunodeficient mice confirmed that TGFβ-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versus-host disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor-expressing T cells generated in the presence of exogenous TGFβ were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGFβ in memory T-cell differentiation and indicates that TGFβ signaling may be harnessed to program Tcm differentiation in the context of ex vivo T-cell stimulation for adoptive immunotherapy in humans.

Highlights

The integration of stimulatory signals during T-cell activation programs the differentiation of effector and memory T cells
According to the progressive differentiation model, T cells differentiate depending on the nature and strength of activation signals following a one-way linear path from na€ve to early memory, effector memory (Tem), and terminally differentiated effector T cells
the accumulation of early/central memory (Tcm) accumulation Total T cells from healthy donor volunteers were stimulated with plate-bound anti-CD3 and soluble anti-CD28 in the presence or absence of exogenous TGFb

Summary

Introduction

The integration of stimulatory signals during T-cell activation programs the differentiation of effector and memory T cells. Primarily known for its immunoregulatory and antiproliferative properties, TGFb orchestrates both regulatory T-cell (Treg) and inflammatory subset differentiation depending on the presence of additional signals (11--14). This pleiotropy is further exemplified by the contrasting prosurvival effects of TGFb on na€ve and memory T cells, and the proapoptotic and functional inhibitory effects on differentiated Teff (15--17). Memory T-cell Differentiation by TGFb transfer of activated T cells in immunodeficient mice revealed that TGFb exposure in culture conferred an enhanced capacity to expand, persist, and mediate xenogeneic graft-versus-host disease (GVHD), as previously reported for cells with Tscm features [3]. The TGFb pathway can be used to program early memory differentiation in human T cells and has, immediate relevance for the field of adoptive immunotherapy

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest