1.3 DC interacts with T cells at the immune synapse
The activation of T cells by DC is mainly through the interaction between DC and T cells, and the formation of immune synapses is the most important feature of this process. The immune synapse is a special structure formed at the cell-cell contact interface when APC and T cells interact [53-54]. In this process, DC provides three key signals.
The initial signal is generated when T cells recognize homologous peptide antigens presented on MHC I or MHC II on the surface of DC through their T cell receptor (TCR)[55-58]. MHC I molecules bind to CD8+ Tn cells, and MHC II molecules bind to CD4+ Tn cells to present specific antigens to the Tn [59]. MHC, antigen and TCR interaction triggers the activation of T cells, initiating downstream signasl via the immune receptor tyrosine-based activation motif (ITAM)[60]. Subsequently, in addition to the MHC-antigen-TCR complex, a second costimulatory signal is required to initiate and maintain T cell activation and proliferation. The second signal can be divided into costimulatory molecules and co inhibitory molecules according to different effects[61-62]. The key costimulatory molecules involved in T cell activation include CD28 (binding to CD80/86 on DC), ICOS (binding to icosl on DC), OX40 (binding to OX40L on DC), and CD40L (binding to CD40 on DC), all the key signaling molecules are responsible for T cell activation, differentiation, and survival. The costimulatory signals cooperate with MHC-antigen -TCR complexes to enhance T cell activation. For instance, the costimulatory molecule CD28 is an important signaling molecule that determines the quality and quantity of T cell immune response[63-64]. In addition, after CD28 activation, PI3K/Akt and other signals are induced to promote the proliferation and development of Tn. Consequently, Tn-Tscm-Tcm-Tem-Tte forms the initial immune response and memory immune response, enabling the body to respond to both the “old” antigens generated by tumor recurrence and the “new” antigens generated by tumor variation[65-66]. After CD28 activating, followed by activating PI3K/Akt [67], NF-κB[68] and other signaling pathway,Tn and Tm then complete their development, differentiation, and proliferation, forming effector T cells to kill tumors and other pathogens. Contrarily,T lymphocyte-associated protein 4 (CTLA-4) competes with CD28 for binding to CD80/86 on DC while PD-1 binds to programmed cell death ligand 1 (PD-L1) on the surface of DC, inhibiting the activation signals[69-70]. Positive and negative costimulatory molecules interact to effectively start, moderately effect, and timely terminate the immune response[71]. The third signal in the form of cytokines secreted by DC is triggered once T cells receive MHC antigen TCR complex signals and sufficient costimulation[72-73]. Combined with T cells, DC can secrete plenty of IL-12 and IL-18. In addition, DCs are dominant partners of T cells and necessary for activating the proliferation of T cells, inducing CTL production, dominating priming of Th1 type immune response, and facilitating tumor clearance [74-76].