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. 2020 Dec 14;11:594841. doi: 10.3389/fimmu.2020.594841

Figure 2.

Figure 2

Activation and limitation of the adaptive immune response: physiological concepts. To activate a naive TL during adaptive immune response, APC must present an antigen through MHC to the TCR (signal 1), but also provide an essential co-stimulation signal (signal 2). These co-stimulation molecules, whose expression are induced during innate immune response, are mainly CD80/CD86 (expressed on APC), and CD28 (expressed on T lymphocyte). The activated TL can then proliferate, differentiate into an effector TL, leave the lymph node and move into peripheral tissues to the inflammatory site. Without this co-stimulation, the TL becomes anergic. To limit the immune response to a pathogenic antigen, both central and peripheral immune control checkpoints exist. Three to 5 days after activation, TLs physiologically express co-inhibitory receptors (immune checkpoint inhibitors; ICPIs) on their surface, such as CTLA-4 and PD-1. CTLA-4 is expressed by naive TLs residing in the lymph nodes, competes with CD28 and interacts with CD80/86: this regulates the amplitude of TL activation and limits the initial immune response. PD-1 is expressed on effector T lymphocytes and interacts with its ligands (PD-L1/PD-L2). PD-1 expression occurs within 24 h after T-cell activation and decreases with antigen clearance. Unlike CTLA-4, its role is to limit, through various signaling pathways, the immune response in peripheral tissues during the active phase of inflammation by decreasing TL activity (exhaustion). TL exhaustion is a progressive process consisting in an effector TL dysfunctional state upon repeated or prolonged stimulation by an antigen, happening in a context of chronic inflammation (chronic infection or cancer) with persistent TL stimulation. The expression of PD-L1 is induced by pro-inflammatory cytokines such as IFNγ or TNFα through a negative feedback loop, thus avoiding collateral damage on tissues. APC, Antigen Presenting Cell; CTLA-4, Cytotoxic T lymphocyte-associated Antigen 4; IFNγ: Interferon Gamma; IL-2, Interleukine 2; MHC, Major Histocompatibility Complex; PD-1, Programmed Death 1; PD-L1, Programmed Death Ligand 1; TCR, T-cell Receptor; TNFα, Tumor Necrosis Factor Alpha.