4-1BB Signaling in T Lymphocytes

The activation of a naive T-Cell requires two signals: ligation of the TCR (T-Cell Receptor) with the MHC (Major Histocompatibility Complex)/peptide complex on the APC (Antigen Presenting Cell) and cross-linking of costimulatory receptors on the T-Cell with the corresponding ligands on the APC. Cross-linking of CD28 on T-Cells with B7-1 and/or B7-2 on the APC is one such critical costimulatory event. Several members of the TNFR (Tumor Necrosis Factor Receptor) family on T-Cells also act as costimulatory receptors enhancing T-Cell responses following initial activation.4-1BB, a T-Cell costimulatory receptor induced by TCR activation, is a TNFR family member that is known to evoke various T-Cell responses through TRAF (TNFR-Associated Factor)- mediated activation of NF-κB (Nuclear Factor-κB), p38 MAPK (Mitogen-Activated Protein Kinase), SAPK (Stress-Activated Protein Kinase)/JNK(c-Jun Kinase), or ERK1/2 (Extracellular Signal-Regulated Kinase-1/2). 4-1BB transmits a potent costimulatory signal to both CD8+ and CD4+ T cells, promoting their expansion, survival, differentiation, and cytokine expression. Its ligand, 4-1BBL (4-1BB Ligand), is a membrane protein, which provides a co-stimulatory signal to T-Cells. 4-1BBL is expressed on Antigen Presenting Cells, including activated B-Cells, macrophages, and mature dendritic cells. Interaction between 4-1BB (on T-Cells) and its ligand (on the Antigen Presenting Cells) increases the activity of both Antigen Presenting Cells and T-Cells: Antigen Presenting Cells proliferation, cell adhesion and/or secretion of various cytokines is elicited, and T-Cells proliferation is stimulated.4-1BB/4-1BB ligand can also play a role in the development of TH1 and TH2 (T Helper-1 and -2) responses. The cytoplasmic domain of 4-1BB binds TRAF1 and TRAF2 and also interacts with TRAF3. In T cells, the association of TRAF1 and 2 with 4-1BB requires receptor aggregation. 4-1BB aggregation induces TRAF2-mediated ASK1 (Apoptosis Signal-Regulating Kinase-1) recruitment and activation. ASK1 activates both the JNK/SAPK and the MAPK pathway. 4-1BB also influences cell survival by activating the NF-κB (Nuclear Factor-KappaB) pathway by interacting with TRAFs. TRAFs, once activated activates NIK(NF-κB-Inducing Kinase), which in turn activates IKKs (Inhibitor of κB Kinase-α), which triggers the degradation of I-κB, thus leading to NF-κB release and translocation to the nucleus. Inside the nucleus, NF-κB binds DNA at κ-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine) and induce gene expression. Besides NF-κB, NIK also activates MAPKs via MEKKs (MAP/ERK Kinase Kinases) and MKKs (MAP Kinase Kinases) respectively. In CD8+ T cells, 4-1BB promotes survival by stimulating antiapoptotic gene expression via the I-κB-α/NF-κB pathway, whereas 4-1BB-mediated expansion results from increasing cell cycle-related gene transcription and translation through the combined action of the ERK1/2 and IL-2R (Interleukin-2 Receptor)/PI3K (Phosphatidylinositide-3 Kinase) /Akt /mTOR (Mammalian Target of Rapamycin) /p70S6K (p70 Ribosomal -S6 Kinase) pathways. 4-1BB-mediated signaling plays a role in T-Cell proliferation in preventing activation-induced cell death, promoting rejection of cardiac and skin allografts, eradicating established tumors, enhancing Integrin-mediated cell adhesion, and increasing T cell cytolytic potential.