Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?

Five interactions between the tumour-necrosis factor receptor (TNFR)–TNF family members have emerged as positive regulators of T cells: OX40–OX40 ligand (OX40L), 4-1BB–4-1BBL, CD27–CD70, herpes-virus entry mediator (HVEM)–LIGHT and CD30–CD30L. The co-stimulatory TNFR-family members are mainly expressed by T cells and their ligands by antigen-presenting cells (APCs).There are two patterns of expression of the co-stimulatory TNFR-family molecules: constitutive (such as CD27 and HVEM) and inducible (such as OX40, 4-1BB and CD30). All can potentially participate in T-cell responses either at the time of T-cell activation or within the first few days of activation.In vitro and in vivo data indicate that HVEM–LIGHT interactions promote the early activation and clonal expansion of T cells, CD27–CD70 might also help to maintain early proliferation, OX40–OX40L and 4-1BB–4-1BBL and CD30–CD30L seem to regulate later expansion of T-cell numbers at the peak of the response.Co-stimulatory TNFR-family signalling seems to regulate T-cell division, survival and effector function by activating nuclear factor-κB (NF-κB), JNK pathways and phosphatidylinositol 3-kinase (PI3K)–protein kinase B (PKB) pathways.It is not clear whether all the TNFR-family molecules are required to function together (simultaneously or sequentially) to regulate a response or whether different responses require different co-stimulatory interactions.Survival signals from TNFR-family members might be crucial for secondary responses and the maintenance of T-cell memory.Blocking co-stimulatory TNF family members might be of benefit in inflammatory and autoimmune diseases and in preventing transplant rejection, whereas promoting these interactions might enhance antitumour immunity.