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Mechanisms of Host Defense
Summary: Ruslan Medzhitov is interested in the analysis of the immune system, inflammation, gene regulation, and host-pathogen interactions.
The immune systems of humans and other vertebrates have two components: innate and adaptive. The innate immune system is evolutionarily ancient and is found in one form or another in all metazoans. Adaptive immunity is present only in vertebrates. The two systems use fundamentally different strategies to recognize invading pathogens. Innate immune receptors recognize conserved macromolecules of microorganisms that are structurally distinct from host macromolecules. Therefore, innate immune receptors can discriminate between self and nonself and are specifically activated only when a pathogen is present. The receptors of the innate immune system are therefore referred to as pattern-recognition receptors because they recognize conserved pathogen-associated molecular patterns (PAMPs).
Adaptive immune recognition, on the other hand, relies on two types of antigen receptors: T cell receptors (TCRs) on T cells and immunoglobulin (Ig) receptors on B cells. These antigen receptors are generated by random somatic gene rearrangement and are expressed in a clonal fashion on lymphocytes. Because the specificity of these receptors is generated randomly, the receptors of the adaptive immune system cannot determine the origin (self or nonself) of the antigen for which they are specific. Consequently, to become activated and differentiated into an appropriate class of effector cells that provide protection from infection, T and B lymphocytes require instructions from the innate immune system. There are several types of instructive signals, and we are interested in their analysis.
A family of pattern-recognition receptors called Toll-like receptors (TLRs) plays a critical role in innate immune recognition. These receptors recognize PAMPs such as bacterial lipopolysaccharide (LPS), lipoteichoic acids, and viral nucleic acids, and thus function as sensors of microbial infection. Upon recognition of PAMPs, TLRs induce inflammatory responses and a variety of antimicrobial effector responses. In particular, TLR ligation on specialized antigen-presenting cells called dendritic cells (DCs) directly induces a differentiation program, called DC maturation, which is characterized by the induction of costimulatory molecules on the cell surface. The costimulatory signal "flags" the antigenic peptides as foreign and is required (along with the TCR ligand–MHC/peptide complex) for the activation of T lymphocytes. Thus, by recognizing microbial molecular patterns, TLRs couple recognition of infection with the induction of pathogen-specific adaptive immune responses.
Innate Immune Recognition and Control of Adaptive Immunity
Adaptive immune response against infectious agents is generally beneficial for the host. However, the response against self-antigens or innocuous nonself-antigens is detrimental, as it can lead, respectively, to autoimmune diseases and allergy. The immune response against these antigens is normally avoided as a result of several mechanisms of immunological tolerance. Central tolerance is a process that eliminates developing lymphocytes that are specific to certain self-antigens. Peripheral tolerance prevents mature lymphocytes from reacting against self-antigens. At least three mechanisms of peripheral tolerance are known: control of costimulatory signals, tolerogenic dendritic cells, and control by regulatory T cells. We are investigating how these seemingly distinct mechanisms of tolerance are functionally related to each other, and how they are controlled by the innate immune system. This knowledge should help us to understand the common themes and mechanisms of autoimmune diseases.
TLRs, Endosomal Trafficking, and Self/Nonself-Discrimination
One puzzle regarding the costimulatory pathway of self/nonself-discrimination is how costimulatory signals are induced on dendritic cells that have phagocytosed self-antigens, usually in the form of apoptotic cells. Since uptake of apoptotic cells is thought to occur continuously, this presents a problem for discriminating between antigens of different origin (self and nonself), as both would be presented with the costimulatory signal.
We recently identified a mechanism that helps to resolve this paradox when we found that TLRs control the fate of phagosomes and phagosomal contents. Moreover, TLR-mediated signaling is phagosome-autonomous, in that TLR ligation on a given phagosome does not affect the maturation pathway of other phagosomes in the same cell. This control of phagosome maturation determines whether antigens derived from a given phagosome will be used to generate ligands for TCRs. Thus TLR-mediated control of phagosome maturation contributes to self/nonself-discrimination by dendritic cells. We are investigating mechanisms responsible for the regulation of phagosomal trafficking by TLR signaling. We are also studying a related problem—how TLR activation in different cellular compartments (plasma membrane versus endosomes) triggers distinct signaling pathways.
TLRs, Inflammation, and Metabolism
Chronic, low-grade inflammation underlies many pathological conditions, including insulin resistance, obesity, and diabetes (so called metabolic syndrome). The mechanisms responsible for the induction of inflammation are unknown, however. We are interested in understanding these mechanisms and, in a broader context, how the inflammatory response is induced by different conditions, including tissue injury and tumor growth.
Regulation of Inducible Gene Expression
Activation of macrophages by TLR ligands leads to transcriptional induction of hundreds of genes. These genes fall into multiple categories, based on their functions and mechanisms of regulation, and different types of chromatin modifications are induced by TLR signals in a gene-specific manner. We are interested in using macrophages as a model system to understand general principles of inducible gene expression.
TLRs and Host-Commensal Interactions
Microbial macromolecules recognized by TLRs are common to entire classes of microorganisms, whether they are pathogenic or commensal (e.g., LPS is made by all gram-negative bacteria). This makes it difficult to distinguish between commensal and pathogenic bacteria. Uncontrolled immune response to commensal intestinal microflora can lead to inflammatory bowel disease. We have found, however, that the interaction of commensal bacteria with TLRs plays an essential physiological role in intestinal epithelial homeostasis and protection from epithelial injury. This suggests an evolutionary relationship between immune defense and host-commensal interactions, and reveals a novel aspect of pathophysiology of intestinal inflammatory disorders.
Last updated: July 26, 2007
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