Fig. 1

a The involvement of native CD28 and 4-1BB costimulation in T cell activation. T cell activation requires two signals. The first is provided by recognition of a specific peptide antigen held by MHC class II on the surface of an antigen presenting cell (APC) by the T cell receptor (TCR) complex. Professional APCs also provide a second signal through engagement of costimulatory molecules on the surface of the T cell; this second signal is essential for survival and expansion of the T cell. This figure highlights two costimulators; CD28, which is recognized by APC surface proteins CD80 and CD86 and 4-1BB, which is recognized by APC surface protein 4-1BBL. Created with BioRender.com. b A simplified representation of the integration of TCR signaling with costimulatory signals. The primary contact between the T cell and the APC is via the TCR/CD3 complex on the T cell and the MHC/peptide complex on the APC, initiating ‘signal 1’. CD28 and 4-1BB signaling (‘signal 2’) is then triggered by engagement with their ligands on the surface of the APC. This triggers dimerization of CD28, or trimerization of 4-1BB, resulting in recruitment of a variety of signaling molecules on the cytosolic side of the T cell membrane. It is important to note that the downstream signals from the TCR/CD3 complex overlap with those from CD28 and 4-1BB, notably via the PKCθ and AKT pathways. This in turn ultimately leads to transcription and translation of genes required to drive cytokine production (particularly IL2 and IFNγ), T cell proliferation and anti-apoptotic signals. Created with BioRender.com