RICERCA ITALIANA     

Interractins between innate and adaptive immunity: from biology to clinic

Università degli Studi di Roma "La Sapienza"

Abstract

The innate immune system not only delivers immediate effectors to control invading pathogens, but also generates regulatory signals to promote adaptive immune responses. Natural killer (NK) and dendritic cells (DC) are among the major players linking innate and adaptive immunity. Although these cells were initially considered unable of specific recognition, accumulating evidence indicate that they use a wide arrays of invariant receptors to recognize molecular patterns demarcating infectious non self as well as normal and abnormal self. These receptors may either induce or inhibit an immune response depending on the meaning of the signals. This proposal is aimed at evaluating:

- The role of activating and inhibitory receptors, and of adhesion molecules in the regulation of NK cell functions and the signalling pathways initiated by these receptors.
- The activity of novel adjuvants and co-stimulatory molecules in the DC-mediated priming of NK and T cell-mediated responses and in the cross-talk between NK and T cells.
- The requirements for optimizing DC cross-presentation of exogenous antigens.
- The relevance in clinical settings such as primary immunodeficiences or bone marrow transplantation of NK or DC-mediated functions.

A deeper knowledge of the molecular and cellular mechanisms linking innate and adaptive immunity will be instrumental for a more rational design of vaccines.

Principal Investigator

Angela SANTONI Universita' degli Studi di ROMA

Research Objectives

The innate immune system not only delivers immediate effectors to control invading pathogens, but also generates regulatory signals to promote adaptive responses. Among the effector cells of innate immunity, natural killer (NK) cells play a pivotal role in the early phase of immune responses against certain intracellular pathogens and tumors by exhibiting cytotoxic functions and secreting a number of cytokines. An essential link between innate and adaptive immunity is provided by dendritic cells (DC) that function as immunological sensors alert to collect dangerous signals and convey them to naive T cells. This function requires DC maturation that is regulated by different microbial products and microenviromental cytokines. DC can also tune the immune response by modulating either the amplitude or the class.
Cells of innate immunity have been considered "non specific", but phagocytes and DC are endowed with a wide array of invariant receptors including Toll-like receptors (TLR) capable of interacting with the classical "microbial" adjuvants. The ability of TLR to recognize "endogenous" adjuvants released by stressed or damaged cells has been less elucidated. NK cell recognition is mainly based on the detection of both self MHC class I molecules and abnormal self. While self MHC class I antigens are mainly coupled to inhibitory pathways, recognition of abnormal self on infected or transformed cells triggers activating receptors. This indicates that the functional >>>

First Results

Identification of novel ligands for orphan non MHC I activating receptors regulating the cytotoxic function of NK cells. - Identification of novel inhibitory receptors and their ligands regulating the cytotoxic function of NK cells. - Identification of the signalling pathways leading to NK cell lysis of different tumor targets. - Identification of the molecular mechanisms regulating ligand-dependent NK receptor down-modulation and their relevance in the attenuation of NK cell responses. - Identification of surface markers of human NK cell maturation.The characterization of the mechanisms underlying the cross-talk between DC and NK cells, and NK cells and T lymphocytes. - The definition of the role of the endocytic processing machinery in the antigen cross-presentation by dendritic cells. -The identification of novel adjuvants capable of directing specific T cell-mediated immune responses. -The signalling events underlying the ability of co-stimulatory molecules such as CD28 to deliver pro-inflammatory signals.The identification of possible defects of dendritic and NK cells that may be important for development of novel prognostic indicators and patient-specific therapeutic strategies.
- A more accurate selection of NK alloreactive donors for haploidentical mismatched bone marrow transplantation. - The development of novel approaches based on the use of alloreactive NK cells to protect from GvHD and reduce the incidence of post-transplant infectious mortality.

Timescale

24 months

National and international background

Protective immunity results from the interplay of two cardinal components: non-specific innate immunity and antigen-specific adaptive immunity. Localized at the epithelial borders, cells of innate immunity recognize non processed antigens using a variety of invariant receptors. The innate immune system is required to deliver immediate effectors to control the invading pathogen and regulatory signals to promote an adaptive immune response (1). The primary components involved in the innate immune response include humoral mediators such as complement and interferons (IFN) alpha and beta, as well as surveillance and effectors cells such as dendritic cells (DC), natural killer (NK) cells and phagocytic cells.
NK cells are effector cells of innate immunity belonging to a distinct lineage of lymphocytes that play an important role in the early phase of immune responses against certain microbial pathogens and tumors by exhibiting cytotoxic functions and secreting a number of cytokines (2). Unlike T lymphocytes, NK cells mediate effector functions spontaneously without the need for prior sensitization and in a non MHC class I-restricted fashion. NK cell functions are augmented by several cytokines including IFN alpha and beta, IL-12, IL-18, IL-2 and IL-15. IFN-gamma-producing NK cells regulate innate resistance by activating phagocytic cells and shape adaptive immunity toward a T helper-1 (Th1) immune response.
Dendritic cells represent the essential link >>>