Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance

Abstract

Natural IFN-␣/␤ producing cells (IPCs) play a central role in innate immunity against microbial infections. In primary immune responses, toll-like receptors (TLRs), as major pattern-recognition receptors, are essential for IPCs as well as other antigen presenting cell (APC) subsets to recognize microbes. IPCs unequivocally express TLR7 and TLR9, and can respond to the respective ligand to produce IFN-␣/␤ and to rapidly differentiate into dendritic cells (DCs). Thereby, IPCs can not only activate innate immune system but also provoke T cell responses. Thus, IPCs link innate and adaptive immunity through TLR system. In addition, recent work has revealed the regulatory system of DC subsets in response to microbial invasion. In this context, by the different but complementary expression profile of TLRs, IPCs together with myeloid APC subsets constitute a rational system of immune surveillance that can cover a wide variety of pathogens and enlarge immune adjuvant effects.

The Functional Effects of Physical Interactions among Toll-like Receptors 7, 8, and 9

“…It adds more complexity to study functional interactions among TLR7, TLR8, and TLR9 as they are all localized to the same intracellular compartment (10) and expressed in different combinations in different immune cells (25,26,28). Also, use of immune cells lacks the control for comparison of the function of one TLR in the absence and presence of the other TLR.…”

“…In human immune cells, the expression of both TLR7 and TLR9 in a given cell type is restricted mostly to plasmacytoid dendritic cells (pDC) and B cells (25)(26)(27)(28). Both TLR7-and TLR9-selective agonists induce type I interferon in pDCs (9,34) and B cell proliferation (35)(36)(37).…”

“…In humans, among TLR7, TLR8, and TLR9, pDCs express TLR7 and TLR9 (25)(26)(27)(28), and myeloid DCs (mDCs) express TLR8 but not TLR7 or TLR9 (27). However, the expression of both TLR7 and TLR8 in a given cell type is restricted to only monocytes (25) and neutrophils (40).…”

“…Several factors, alone or in combination, may have hindered these types of studies. The most notable are as follows: 1) the lack of agonists that selectively activate either TLR7 or TLR8, as their cognate agonist single-stranded RNAs activate both the receptors (7,8); 2) activation of either TLR7 or TLR8 by single-stranded RNA requires transfection of the agonist, and the innate immune system is known to have other intracellular molecular mechanisms that recognize RNAs and activate signaling (22,23); 3) very little is known about the role of TLR8 in innate immunity as it is inactive in the mouse (24), thus limiting the studies to only human cells that offer very little opportunity for any genetic manipulations; and 4) in almost all instances, the cells that express TLR7 also express TLR9 (25)(26)(27)(28), and the activation of either of these receptors leads to similar immunological response (29), confounding the effects of any possible interaction of one on the other. Finally, any immune or nonimmune cells that express multiple TLRs are not suitable for comparison of the function of one TLR in the absence and presence of the other TLR.…”

Pattern recognition receptors: A contemporary view on liver diseases

“…This is in agreement with previous observations that immune cells are the main producers of type 1 IFNs and stimulation via TLR 3, 4,7, 8 and 9, but not TLR2, leads to production of IFN␣, suggesting that endogenous IFNs play a critical role in anti-viral defense. 107 Indeed, type 1 IFN and IFN-inducing TLR ligands (CpG) could be successfully used as therapeutic agents in viral hepatitis, [108][109][110] or as potent adjuvants for anti-HBV vaccines, as shown both in animal models and in humans. [111][112] However, increasing evidence suggest that viruses may use PRRs to escape immune surveillance.…”