Contribution of T- and B-cell intrinsic toll-like receptors to the adaptive immune response in viral infectious diseases

Abstract

Toll-like receptors (TLRs) comprise a class of highly conserved molecules that recognize pathogen-associated molecular patterns and play a vital role in host defense against multiple viral infectious diseases. Although TLRs are highly expressed on innate immune cells and play indirect roles in regulating antiviral adaptive immune responses, intrinsic expression of TLRs in adaptive immune cells, including T cells and B cells, cannot be ignored. TLRs expressed in CD4 + and CD8 + T cells play roles in enhancing TCR signal-induced T-cell activation, proliferation, function, and survival, serving as costimulatory molecules. Gene knockout of TLR signaling molecules has been shown to diminish antiviral adaptive immune responses and affect viral clearance in multiple viral infectious animal models. These results have highlighted the critical role of TLRs in the long-term immunological control of viral infection. This review summarizes the expression and function of TLR signaling pathways in T and B cells, focusing on the in vitro and vivo mechanisms and effects of intrinsic TLR signaling in regulating T- and B-cell responses during viral infection. The potential clinical use of TLR-based immune regulatory drugs for viral infectious diseases is also explored.

Keywords: Adaptive immune response; B cells; Immunotherapy; T cells; Toll-like receptor; Viral infection.

Fig. 1

Interaction of TLR and TCR signaling pathways in T cells. Activation of naïve CD4 + and CD8 + T cells is initiated by recognition of the TCR and MHC/peptide complex. TCR signaling is transmitted by the CD3 molecule and then i.a. activates the PI3K/Akt/mTOR pathway, leading to the reprogramming of energy metabolism and activation of transcription factors, such as NF-κB, NFAT, and AP1. These transcription factors control the differentiation of T cells, the downstream production of cytokines, and upregulate the expression of TLRs (left panel). In the activated T cells, engagement of TLR agonists and TLRs initiates downstream signal cascades by recruiting adaptor proteins such as MyD88 or TRIF, leading to enhanced activation of PI3K/Akt/mTOR pathway, upregulated energy metabolism, and activates the transcription factors such as NF-κB and IRF4 to regulate the production of proinflammatory cytokines and chemokines (right panel). TLRs expressed in CD4 + and CD8 + T cells serve as costimulatory molecules in enhancing TCR signal-induced T-cell activation and function survival

Fig. 2

Activation of T cells by TLR engagement. Activation of naïve T cells requires at least two signals by interaction with APCs, including (1) The primary TCR signaling that was initiated by recognition of the MHC/peptide complex or antigen; (2) Secondary signals mediated by the interaction of costimulatory with their ligands. Primary and secondary signaling induces the activation of naïve cells and improve the expression of TLRs on the T cells. In addition, (3) engagement of TLRs with their agonists provides additional signals to enhance TCR signaling (upper left panel). TLR signaling alone may induce partial activation of naïve T cells, but more conclusive evidence is needed (lower left panel). Activated or effector T cells undergo reactivation upon recognizing viral-specific antigens presented on APCs and activates the TCR signaling, costimulatory signaling and TLR signaling from TLR agonists derived from pathogens, resulting in rapid and vigorous proliferation and cytokine production (upper right panel). At the site of infection, effector T cells recognize the antigens on the target cells which lack of the costimulatory molecules. Virus-derived TLR agonists engage with TLRs in T cells and provide alternative secondary signals for the T cell proliferation, cytokine production and cytotoxic activities of T cells (lower right panel)