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].