Normal And Pathologic Mechanisms Of Inflammation, Innate And Acquired Immunity

Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

TGF-beta, Th17 and regulatory T cells in the control of infectious, immune and neoplastic diseases:[unreadable] Naturally occurring and inducible regulatory T cells (Treg), in addition to inducible/adaptive Tr1 and Th3 cells, are fundamental in the control of immune responsiveness to self and nonself antigens. Characterized by membrane expression of CD4, CD25, GITR, CTLA-4, TGF-beta and TGF-beta receptor type II, all of which contribute to their unique functional repertoire, Treg specifically express the transcription factor Foxp3. We have previously shown that generation of these cells in vitro and adoptive transfer into experimental animals with immune-mediated mucosal pathology alleviates the symptoms of disease. Recent evidence also implicates Treg in control of innate immune responses, including suppression of natural killer (NK) cells. It is also evident that whereas an increase in Treg is beneficial in autoimmune and antigen-driven pathologies where insufficient numbers are contributory, an over-representation of these cells can also be detrimental, especially evident in infectious and neoplastic diseases. In this regard, we have identified a high level of expression of TGF-beta in cells infiltrating tumor tissues, in addition to an abundance of Foxp3+ cells in association with these tumors. These Treg may contribute to the failure of immune surveillance to detect and/or eliminate such tumors and be a potential target in promoting immune-mediated tumor therapy. New evidence reveals that TGF-beta provides a unique and essential trigger for T helper lymphocyte 17 (Th17) lineage commitment. Th17 generating cells are instrumental in embellishing innate pathways and in the evolution of autoimmune disease, linking TGF-beta with both induction and suppression of an immune response.[unreadable] [unreadable] Secretory Leukocyte Protease Inhibitor - an Innate Immunomodulatory Molecule:[unreadable] Effective host defense against intracellular pathogens relies upon activation of both innate and adaptive immune responses to contain or eliminate the infectious microbe. Equally important are regulatory mechanisms to terminate exuberant responses to restore homeostasis in the immune system. SLPI is a potent serine protease inhibitor with both anti-microbial and anti-inflammatory functions and is found in fluids associated with mucosal surfaces of the oral, nasal, respiratory, and reproductive tracts. Furthermore, SLPI is produced by mouse macrophages but also inhibits macrophage activation by suppressing NFkB-dependent signaling pathways. The combination of SLPIs microbicidal activity and suppressive activity on pathogen-mediated immune responses implicate this molecule in innate host defense and the SLPI null mouse provides a model to explore the in vivo role for SLPI in inflammatory responses and host defense. Using a model of mucosal asthma, SLPI was found to be protective from development of allergen-induced airway hyperreactivity and disease was exacerbated following ablation of SLPI. To determine how SLPI participates in defense against infectious pathogens, SLPI null and wildtype mice were infected with bacteria (Streptococcus pneumoniae, Staphylococcus aureus) or an intracellular parasite Leishmania major in a model of cutaneous leishmaniasis. In contrast to C57Bl/6 SLPI wildtype littermates which develop self-healing skin lesions at the site of L. major inoculation, SLPI null mice develop an exacerbated chronic infection with increased lesion size and parasite numbers that results in systemic spread of parasites. Whereas spontaneous healing of lesions in SLPI wildtype mice involves a Th1-dominant cytokine response, elevated suppressive Th2 cytokines IL-4, IL-10 and TGF-beta in SLPI null mice likely contribute to the failed host response, despite persistently elevated levels of IFN-gamma. Similarly, in bacterial infections, ablation of SLPI is associated with exaggerated, but ineffective immune responses. These studies highlight a protective role for SLPI in infectious diseases and reveal its potential as a therapeutic agent for the treatment of inflammatory and infectious diseases.