The TNF–TNFR Family of Co-signal Molecules

  • Takanori SoEmail author
  • Naoto Ishii
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1189)


Costimulatory signals initiated by the interaction between the tumor necrosis factor (TNF) ligand and cognate TNF receptor (TNFR) superfamilies promote clonal expansion, differentiation, and survival of antigen-primed CD4+ and CD8+ T cells and have a pivotal role in T-cell-mediated adaptive immunity and diseases. Accumulating evidence in recent years indicates that costimulatory signals via the subset of the TNFR superfamily molecules, OX40 (TNFRSF4), 4-1BB (TNFRSF9), CD27, DR3 (TNFRSF25), CD30 (TNFRSF8), GITR (TNFRSF18), TNFR2 (TNFRSF1B), and HVEM (TNFRSF14), which are constitutive or inducible on T cells, play important roles in protective immunity, inflammatory and autoimmune diseases, and tumor immunotherapy. In this chapter, we will summarize the findings of recent studies on these TNFR family of co-signaling molecules regarding their function at various stages of the T-cell response in the context of infection, inflammation, and cancer. We will also discuss how these TNFR co-signals are critical for immune regulation and have therapeutic potential for the treatment of T-cell-mediated diseases.





antigen-presenting cell;


chimeric antigen receptor




cytotoxic T lymphocyte


cytotoxic T-lymphocyte-associated protein-4


dendritic cell


decoy receptor 3


death receptor 3


experimental autoimmune encephalomyelitis


Epstein–Barr virus


germinal center


glucocorticoid-induced TNFR family-related protein


graft-versus-host disease


human papillomavirus


herpesvirus entry mediator


inducible T-cell costimulator


lymphocytic choriomeningitis virus


homologous to lymphotoxins (LTs), inducible expression, which competes with herpes simplex virus glycoprotein D (HSV gD) for HVEM, a receptor expressed on T lymphocytes


monoclonal antibody


mitogen-activated protein kinase


nuclear factor-kappa B


programmed cell death-1


systemic lupus erythematosus


T-cell receptor


T follicular helper










TNF-like ligand 1A


Toll-like receptor


tumor necrosis factor


tumor necrosis factor receptor 2


TNF receptor superfamily


TNF superfamily


TNF receptor-associated factor

Treg cells

Foxp3+ CD25+ CD4+ regulatory T cells



This work was supported by JSPS KAKENHI Grant Numbers 24590571 (to T.S.), 15H04640 (to T.S.), 18H02572 (to T.S.), 24390118 (to N.I.), 15H04742 (to N.I.), and 16K15508 (to N.I.), as well as by grants from the Takeda Science Foundation (to T.S.), the Suzuken Memorial Foundation (to T.S.), the SENSHIN Medical Research Foundation (to T.S.), the Astellas Foundation for Research on Metabolic Disorders (to T.S.), the Yamaguchi Educational and Scholarship Foundation (to T.S.), and the Daiichi-Sankyo Foundation of Life Science (to N.I. and T.S.).


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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyTohoku University Graduate School of MedicineSendaiJapan
  2. 2.Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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