Tregs from human blood differentiate into nonlymphoid tissue–resident effector cells upon TNFR2 costimulation
Mark Mensink, Lotte J. Verleng, Ellen Schrama, George M.C. Janssen, Rayman T.N. Tjokrodirijo, Peter A. van Veelen, Qinyue Jiang, M. Fernanda Pascutti, Marie-Louise van der Hoorn, Michael Eikmans, Sander de Kivit, Jannie Borst
Mark Mensink, Lotte J. Verleng, Ellen Schrama, George M.C. Janssen, Rayman T.N. Tjokrodirijo, Peter A. van Veelen, Qinyue Jiang, M. Fernanda Pascutti, Marie-Louise van der Hoorn, Michael Eikmans, Sander de Kivit, Jannie Borst
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Research Article Immunology

Tregs from human blood differentiate into nonlymphoid tissue–resident effector cells upon TNFR2 costimulation

Abstract

Tregs can facilitate transplant tolerance and attenuate autoimmune and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg expansion and function in vivo and to create therapeutic Treg products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naive, thymus-derived Tregs (tTregs) from human blood that promotes their differentiation into nonlymphoid tissue–resident (NLT-resident) effector Tregs, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue–resident (LT-resident) Treg phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ tTregs and conventional T cells (Tconvs), followed by bioinformatic comparison with published transcriptomic Treg signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promoted tTreg capacity for survival, migration, immunosuppression, and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTregs. Flow cytometry validated the presence of the TNFR2-driven tTreg signature in effector/memory Tregs from the human placenta, as opposed to blood. Thus, TNFR2 can be exploited as a driver of NLT-resident tTreg differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.

Authors

Mark Mensink, Lotte J. Verleng, Ellen Schrama, George M.C. Janssen, Rayman T.N. Tjokrodirijo, Peter A. van Veelen, Qinyue Jiang, M. Fernanda Pascutti, Marie-Louise van der Hoorn, Michael Eikmans, Sander de Kivit, Jannie Borst

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Figure 5

Costimulated tTregs acquire an effector Treg profile without Th-like polarization.

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Costimulated tTregs acquire an effector Treg profile without Th-like pol...
(A) Scheme depicting naive CD4+ Tconv effector differentiation into Tfh, Th1, Th17, and Th2 lineages, with defining transciption factors, chemokine receptors, and cytokines. (B) Representative plots showing gating strategy to identify CD25hiCD127lo Tregs among CD4+ T cells from PBMCs (left) and gating strategy to identify CD45RA+RO– naive tTregs among total Tregs from PBMCs (right). (C) Left: Intracellular FOXP3/Helios expression (left) and cell surface naive/memory marker expression (right) for naive tTregs (black) and CD28-costimulated (blue) and TNFR2-costimulated (red) tTregs. (D) Top: Representative plots showing expression of Th lineage–associated markers (A) on naive, CD28-costimulated, or TNFR2-costimulated tTregs. Bottom: Positive controls showing expression of the analyzed markers on indicated cell populations, as measured directly ex vivo. (E) Representative assessment of the capacity of CD28- or TNFR2-costimulated tTregs to produce Th lineage–associated cytokines after PMA/ionomycin-based restimulation (top), with positive staining controls as indicated (bottom). (B–E) Data are representative of n = 5.