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 6

Enrichment of healthy NLT Treg gene signatures in TNFR2-costimulated tTregs.

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Enrichment of healthy NLT Treg gene signatures in TNFR2-costimulated tTr...
(A) GSEA plots showing enrichment of indicated published Treg gene signatures from healthy tissues and peripheral blood (40, 46–49) in the transcriptomes of tTregs costimulated via TNFR2 or CD28 for 7 days. Normalized enrichment scores (NES) are depicted (FDR < 0.05). (B) Summary of GSEA data showing enrichment of published Treg gene signatures in healthy tissues (40, 46–49) in the transcriptome of TNFR2- or CD28-costimulated tTregs. Red and blue text mark gene sets describing, respectively, high and low expression in Tregs from indicated tissues. The first author of the corresponding reference is shown between parentheses. Additional information is described in Supplemental Table 2. VAT, visceral adipose tissue. (C) NLT-related gene sets were compared to find overlap, leading to a combined NLT Treg gene signature composed of genes that were present in at least 3 of 9 selected NLT-related gene sets (40, 46–49). Similarly, a combined LT Treg gene signature consisted of genes present in at least 2 of 5 selected LT-related gene sets. The selection of gene sets is shown in Supplemental Table 2. GSEA was performed using the combined NLT and LT Treg signatures, which is displayed together with NES (FDR < 0.05). Leading edge genes are marked by dashed or dotted lines and visualized as STRING networks, including enriched biological processes according to GO/Reactome. Disconnected nodes not associated with labeled processes are not shown.