The TNF family in T cell differentiation and function – Unanswered questions and future directions

• TNF/TNFR superfamily proteins are major regulators of T cells.
• OX40, CD27, GITR, DR3, CD30, 4-1BB, TACI, and TNFR2 promote clonal expansion and T cell memory.
• Fas, TNFR1, and TRAILR promote apoptotic death and limit T cell activity.
• There are many unknowns regarding their function, expression, and integration in T cell responses.
• Knowledge of how they control T cells will help fulfill their promise as targets for clinical therapy.

Proteins in the TNF/TNFR superfamily are recognized as major regulators of the activity of conventional CD4 and CD8 T cells, and also of regulatory T cells (Treg). Stimulatory molecules such as OX40, CD27, GITR, DR3, CD30, 4-1BB, TACI, and TNFR2 can promote division and survival in T cells, enhance effector activity including cytokine production, and drive the generation of T cell memory. They also display the capacity to block the development of inducible Treg cells or inhibit suppressive activity in Treg cells. Additionally, molecules such as Fas, TNFR1, and TRAILR promote apoptotic death in T cells and generally limit T cell activity. Although our knowledge of these proteins is quite good at this point in time, there are still many unknowns regarding their function, their expression patterns, and the involvement of these different molecules at various stages of the T cell response that occurs in autoimmunity, cancer, infectious disease, and during vaccination. Importantly, it is still unresolved how similar or dissimilar each of these receptors are to one another, the extent to which cooperation occurs between family members, and whether alternate TNF–TNFR interactions induce qualitatively different cellular responses. All of the molecules are attractive targets for immunotherapy of human disease, but it is not yet clear how to differentiate between them and make an informed decision as to whether any one protein may be the preferred focus of clinical development for a given specific disease indication. This review will highlight unanswered questions related to these molecules and the biology of T cells, and describe possible future directions for research in this area. Expanding our knowledge of how the TNF/TNFR family control T cells will undoubtedly help fulfill the promise of these molecules for providing efficacious clinical therapy of immune system disease.