Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity

Abstract

Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.

Keywords: T cells; autoimmune diseases; cancer; cell-mediated immunity; infectious diseases; signaling pathway; toll-like receptors.

Figure 1

TLR signaling pathway in innate immune cells. TLR5, TLR4, and the heterodimers of TLR2–TLR1 or TLR2–TLR6 prefer to recognize the membrane components of pathogens at the cell surface, whereas TLR3, TLR7–TLR8, and TLR9 localize to the endosomes, where they recognize the nucleic acids from both the host and foreign microorganisms. TLR4 localizes at the plasma membrane, but it is endocytosed into endosomes upon activation. Upon binding to their respective ligands, TLR signaling is initiated by dimerization of receptors, leading to the engagement of TIR domains of TLRs with TIRAP and MyD88 (or directly interact with MyD88) or with TRAM and TRIF (or directly interact with TRIF). The TLR4 signaling switches from MyD88 to TRIF once TLR4 moves to the endosomes. Engagement of MyD88 recruits the downstream signaling molecules to form Myddosome, which is based on MyD88 and contains IRAK4 and IRAK1/2. IRAK1 further activates the E3 ubiquitin ligase-TRAF6 to synthesize the K63-linked polyubiquitin chains, leading to the recruitment and activation of the TAK1 complex. The activated TAK1 further phosphorylates and activates the canonical IKK complex, ultimately leading to the activation factor NF-κB. The activation of TAK1 also leads to the activation of MAPKs, including MKK4/7 and MKK3/6, which further activate JNK and p38, respectively. The activation of IKKβ also leads to the activation of MKK1 and MKK2, which further activate ERK1/2. The activation of these MAPKs leads to some important transcription factor activations, such as CREB, AP1. These transcription factors cooperate with NF-κB to promote the induction of pro-inflammatory cytokines. Engagement of TRIF recruits the TRAF6 and TRAF3. Activated TRAF6 can recruit the kinase RIP1 and activate the TAK1 complex and IKK complex, leading to the activation of NF-κB and MAPKs. TRIF also promotes the TRAF3-dependent activation of the TBK1 and IKKϵ (originally IKKi), which further phosphorylates and activates IRF3. Among TLR7, TLR8, and TLR9 signaling in pDCs, IRF7 can bind to the Myddosome and is directly activated by IRAK1 and IKKϵ. Activation of IRF3 and IRF7 leads to the induction of Type I IFN.

Figure 2

Promotion of CD4⁺ T cell activation by TLRs on dendritic cells. Once TLR2/4 recognize their individual ligands, they can alter the expression of chemokine receptors (CCR2, CCR5, and CCR7), leading to DC migration from the infected tissue to the draining lymph node, where naïve T cells are stimulated. TLR2/4 signaling can promote the antigen process and bind to the major histocompatibility complex II and be presented to the CD4⁺ T cells, thus providing the first signal for activation of the CD4⁺ T cells. In addition, TLR signaling triggers the up-regulation of costimulatory molecules on the cell surface of DCs, which provide the second signal to activate the antigen-specific CD4⁺ T cells. TLR signaling can also induce the production of cytokines such as IL-12, TNF-α in DCs. These cytokines function as “instructive” cytokines and drive the activation and differentiation of CD4⁺ T cells.

Figure 3

Individual TLR singaling involves in various diseases. Individual TLR-associated infectious diseases (red), autoimmune diseases (green) and cancer (blue) are shown.