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 ecrosis Factor Receptor) family on T-Cells also act as costimulatory receptors enhancing T-Cell responses following initialactivation (Ref.1).
4-1BB (CD137) is a costimulatory molecule transiently expressed on the T-cell surface after TCR engagement, whereas its ligand 4-1BBL can be found on Professional antigen-presenting cells, but more importantly, also on tumor cells. 4-1BB receptor plays a variety of crucial roles: preventing activation-induced cell death, promoting cell cycle progression, enhancing cytotoxicity and the production of type 1 cytokines such as IL-2, IFN-gamma, and TNF-alpha, and increasing the memory CD8+ T cells. 4-1BB signaling also triggers TRAF-dependent NF-KappaB activation to increase the expression of anti-apoptotic proteins including Bcl-2 and Bcl-XL,and activates the PI3K and MEK-1/2 signaling pathway to promote cell cycle progression (Ref.2 and 3).
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 TRAF2 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-KappaB (Nuclear Factor-KappaB) pathway by interacting with TRAFs. TRAFs, once activated activates NIK (NF-KappaB-Inducing Kinase), which in turn activates IKKs (Inhibitor of KappaB Kinase-Alpha), which triggers the degradation of I-KappaB,thus leading to NF-KappaB release and translocation to the nucleus. Inside the nucleus, NF-KappaB binds DNA at Kappa-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-KappaB, 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-KappaB-Alpha/NF-KappaB 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 (Ref.1, 4 and 5).