RICERCA ITALIANA     

Analysis of the ability of Toll-like receptors to modulate effector and regulatory functions of innate immunity components

Università degli Studi di Roma "La Sapienza"

Abstract

The different cell populations of the innate immunity (namely monocyte/macrophages, and Natural Killer (NK) and gamma/delta T lymphocytes) coordinately concur to the early phase of the response against pathogens. Beside the direct antimicrobial activity, which is crucial for the limitation of microbial dissemination, these cell populations also modify the environment of the inflammatory site, and induce the recruitment and the activation of other cell populations, through the rapid secretion of cytokines and chemokines. In fact, multiple immunoregulatory circuits are put into action in the early phase of infection; they lead to the induction, potentiation, and support of the coordinate activities of the different cell populations belonging to the innate response, and set up the cytokine environment which instructs the adaptive response.
In this context, a family of recently identified membrane receptors, the Toll-like receptors (TLR), plays a central role, as they mediate the recognition of highly conserved microbial molecular structures (the pathogen-associated molecular patterns, PAMP), and determine the interaction of innate immunity cell populations with molecular components of pathogens. TLR-triggered cell functions depend on still partially unknown intracellular signalling pathways, and result in the production of proinflammatory cytokines, dendritic cell maturation, and T helper 1-type response polarization; moreover, TLR ligands can also directly modify >>>

Principal Investigator

Gabriella PALMIERI Universita' degli Studi di ROMA

Research Objectives

Natural immunity components (including macrophages, gamma/delta T lymphocytes, and Natural Killer (NK) cells) play a pivotal role in the innate responses against infections, and in the instruction and polarization of the adaptive response. Their ability to perform pathogen killing, or the lysis of infected cells, is crucial for the limitation of microbial dissemination; their immunoregulatory activity relies on the capacity to rapidly secrete cytokines and chemokines, which induce the recruitment and activation of other cell populations at the inflammatory site, and to establish multiple cell-cell interactions, through distinct membrane receptors endowed with either activating, inhibitory, or costimulatory function. The functions of innate immunity cell populations are finely tuned by the interaction with molecular components of pathogens. In this context, a family of recently identified membrane receptors, the Toll-like receptors (TLR), plays a central role, as they mediate the recognition of highly conserved microbial molecular structures (the pathogen-associated molecular patterns, PAMP), and determine the functional activation, differentiation, and cell survival. In particular, TLR3 and TLR9 intracellular receptors, are specific for double stranded RNA (dsRNA) molecules, and unmethylated CpG-rich oligodeoxynucleotides CpG ODN), respectively. Their ability to powerfully activate cells of the innate response may lead to the exploitment of their ligands as adjuvants, in >>>

First Results

The expected results obtained in the first phase of the project will consist of:
- the comprehension of the mechanisms regulating TLR3 and TLR9 expression and modulation on innate immunity effectors;
- the characterization of the role of TLR3- and TLR9-specific ligands on the activation, functions and differentiation of macrophages, NK cells, and gamma/delta T lymphocytes;
- the identification of the main signal transduction pathways initiated by TLR3 and TLR9 in distinct cell populations of innate immunity.The expected results of this second phase of the project will be represented by:
- the establishment of the role of TLR3 and TLR9 ligands in directly or indirectly modulating the interactions and the functional crosstalk between the different components of natural immunity;
- the identification of TLR-triggered signalling events involved in the biogenesis and maturation of macrophage phagolysosome, and in the different functional activities of NK cells;
- the definition of the role of cellular environment in modulating the signalling ability of TLR3 and TLR9;
- the establishment of the role of TLR ligands in affecting NK cell survival.

Timescale

24 months

National and international background

The different cell populations of the innate immunity concur to the early phase of the response against pathogens. Monocyte/macrophages, and Natural Killer (NK) and gamma/delta T lymphocytes, are important effectors of the natural resistance against infections by many intracellular pathogens. Although they have been initially characterized for the direct antimicrobial activities, these cell populations also modify the environment of the inflammatory site, induce the recruitment and activation of other cell populations, and thus contribute to the instruction of the adaptive response, through the rapid secretion of cytokines and chemokines.
Tissue macrophages and circulating monocytes, which rapidly infiltrate the inflammatory site, represent an early warning system for pathogens, by acting as both sentinels and the first line of defense against infections. Besides carrying out the intracellular killing of a variety of microbes, they also secrete a vast array of biological mediators, such as cytokines and chemokines, leading to the coordinated recruitment and activation of other cell populations responsible for microbial eradication (1); they also play a role in the instruction and polarization of adaptive response, by acting as antigen presenting cells to T lymphocytes. Antimicrobial effector functions and immunoregulatory activity of macrophages are finely tuned by soluble mediators and by membrane receptors involved in the interactions with pathogens or with the >>>