Toll‐like receptors: the swiss army knife of immunity and vaccine development

Abstract

Innate immune cells have a critical role in defense against infection and disease. Central to this is the broad specificity with which they can detect pathogen-associated patterns and danger-associated patterns via the pattern recognition receptors (PRRs) they express. Several families of PRRs have been identified including: Toll-like receptors (TLRs), C-type lectin-like receptors, retinoic acid-inducible gene-like receptors and nucleotide-binding oligomerization domain–like receptors. TLRs are one of the most largely studied families of PRRs. The binding of ligands to TLRs on antigen presenting cells (APCs), mainly dendritic cells, leads to APC maturation, induction of inflammatory cytokines and the priming of naive T cells to drive acquired immunity. Therefore, activation of TLRs promotes both innate inflammatory responses and the induction of adaptive immunity. Consequently, in the last two decades mounting evidence has inextricably linked TLR activation with the pathogenesis of immune diseases and cancer. It has become advantageous to harness these aspects of TLR signaling therapeutically to accelerate and enhance the induction of vaccine-specific responses and also target TLRs with the use of biologics and small molecule inhibitors for the treatment of disease. In these respects, TLRs may be considered a ‘Swiss Army' knife of the immune system, ready to respond in a multitude of infectious and disease states. Here we describe the latest advances in TLR-targeted therapeutics and the use of TLR ligands as vaccine adjuvants.

Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

“…Binding of these ligands to TLRs on DCs results in their maturation (139, 140). In addition, TLR9 agonists have been shown to increase T cell infiltration in the CT26 colon cancer model (141).…”

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

“…The role of LTB 4 in TLR activation has been suggested [64–66]. TLR signaling induces pro-inflammatory cytokine responses [67, 68]. TLR2 is a cell surface receptor that senses peptidoglycan molecules commonly found on gram-positive bacteria and TLR9 is an endosomal receptor that detects DNA [67, 68].…”

“…TLR signaling induces pro-inflammatory cytokine responses [67, 68]. TLR2 is a cell surface receptor that senses peptidoglycan molecules commonly found on gram-positive bacteria and TLR9 is an endosomal receptor that detects DNA [67, 68]. LTB 4 stimulation upregulates the expression of TLR2 and TLR9 in human neutrophils [69].…”

Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality?

“…2 The presence of danger signals induced by viral-mediated cytotoxic injury favors the increased expression of positive co-stimulatory signals and the induction of immunologic response. 3 In contrast, a panel of negative co-stimulatory factors, including the programmed cell death ligand 1 (PD-L1)/ programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyteassociated protein 4 (CTLA-4)/CD28, TIM-3/galectin-9, and LAG3, mediate tolerance such that genetic deletion in animal models is associated with autoimmunity. [4][5][6][7][8][9] Tumor cells exploit these biologic mechanisms of tolerance to evade host immunity.…”