Toll-Like Receptor Signaling in the Establishment and Function of the Immune System

Abstract

Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity.

Keywords: TLR; immune system; inborn errors of immunity.

Figure 1

TLR pathway variants and immune deficiencies. TLRs signal via MyD88-dependent or TRIF-dependent pathways. Activated MyD88 recruits IRAKs1/2/4, then TRAF6, and ultimately activates MAPKs and NF-κB resulting in the production of proinflammatory cytokines. Activated TRIF (via ligation of TLR3 or TLR4) binds to TRAF3 and TBK1, ultimately activating IRF3 and IRF7 to stimulate the production of interferons. TRIF also interacts with TRAF6 to stimulate MyD88-independent activation of MAPKs and NF-κB. Highlighted on the left are TLR signaling pathway players in which variants have been associated with specific inborn errors of immunity, as indicated. Created with BioRender.com accessed on 27 April 2021.