ReviewThe role of chemokines in linking innate and adaptive immunity
Introduction
The host response to foreign challenge requires the coordinated action of both the innate and acquired arms of the immune system. The adaptive response is mediated by T and B cells that have undergone germline gene rearrangement, and is characterized by exquisite specificity and long-lasting memory. Innate immunity was formerly thought to be nonspecific, but it has become clear that the innate immune system can recognize pathogens from self.
Once thought of as separate, parallel systems, the innate and adaptive immune systems are now known to be two interdependent parts of a single integrated immune system. The innate immune response not only provides the first line of defense against microorganisms, but also provides the biological context—the ‘danger signal’— that instructs the adaptive immune system to mount a response [1]. The adaptive immune response calls on the innate immune system to provide the professional phagocytes (e.g. macrophages and neutrophils) and specialized granulocytes (e.g. eosinophils and basophils) necessary to engulf small pathogens and contain larger parasites.
The primary adaptive immune response takes place in the draining lymph nodes and not in the tissue itself. Antigen is picked up by dendritic cells in the tissue and carried into regional lymph nodes, where the dendritic cells activate naive T and B cells. Activated T and B cells then leave the lymph node and find their way back to the site of inflammation. Although the trafficking patterns of dendritic cells and lymphocytes have been appreciated for some time, the molecules that control their movement in vivo have only recently been identified as members of the chemokine family (Fig. 1). The chemokine system has emerged as the crucial regulator of the dendritic-cell and lymphocyte trafficking that is needed, first, to bring together antigen-loaded dendritic cells and naive T and B cells to generate an adaptive immune response and, second, to deliver this adaptive effector response to sites of inflammation and infection.
In this review I focus on how innate immune stimuli, through activation of Toll-like receptors (TLRs), induce the expression of a subset of chemokines from resident tissue macrophages and alter chemokine-receptor expression on dendritic cells to link activation of innate immune cells effectively with the generation and delivery of an adaptive immune response. In addition, I discuss the concept that chemokines are used by the adaptive immune system to amplify antigen-specific lymphocyte responses with the destructive power of the innate immune system.
Section snippets
The Toll connection
The innate immune system provides the biological context for the adaptive immune response. Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (i.e. pathogen-associated molecular patterns), which are shared by large groups of microorganisms. TLRs function as PRRs and are essential for translating the recognition of microbial components to activation of the
TLR activation of resident tissue macrophages and dendritic cells
Resident tissue macrophages and dendritic cells play a critical role in initiating the innate immune response in the tissue. These professional phagocytes express many PRRs, including CD14, scavenger receptors and TLRs. These PRRs have the ability to recognize foreign antigens as pathogens and set in motion the innate immune response by activating one or more of the TLRs. TLR activation ultimately leads to the activation of NF-κB — a key transcription factor that mediates early host defenses.
The NK-cell connection
The early pathogen-induced release of MIP-1α and MIP-1β has been shown to be vital for the initial influx of NK cells into the liver in a murine model of cytomegalovirus (CMV) 4., 5••.. These NK cells are an important source of IFN-γ, which induces the expression of the chemokines IP-10 and Mig (CXCL9). In turn, IP-10 and Mig lead to the recruitment of activated T cells into the liver. Neutralization of Mig in this model impaired the ability of the host to control CMV replication and led to
The IP-10 connection
As mentioned above, NK-cell production of IFN-γ is important in inducing the expression of the IFN-γ-inducible chemokines IP-10, Mig and I-TAC (CXCL11). These chemokines bind to and activate CXC-chemokine receptor (CXCR)3, which is expressed on activated CD4+ and CD8+ T cells and NK cells, and is important for the recruitment of these cells into tissues.
IP-10 is also directly induced by bacterial products and viruses, and therefore may play an early role in recruiting the first T cells and NK
Modulation of chemokine-receptor expression
The early pathogen-induced release of MIP-1α and MIP-1β is also involved in attracting immature dendritic cells into the immediate vicinity of the pathogen. Immature dendritic cells act as sentinels in the tissue and pick up foreign antigen very efficiently, but are not yet potent activators of naive T cells [10]. Dendritic cells have been shown to express TLR-2, -3, -4, -5, -6 and -9 and respond to various pathogen-associated molecular patterns, such as LPS, bacterial lipoproteins,
Localization of immature dendritic cells
Cells of the dendritic-cell lineage are now known to be the primary cells responsible for activating naive T and B cells. Dendritic cells, which are formed in the bone marrow, must move into tissues to pick up and respond to foreign antigen. This process is probably under the control of chemokines, but a single chemokine–chemokine-receptor pair has not yet emerged as a dominant player in this process. CCR6 was thought to have a role in this process, but the impairment of dendritic cell function
T-cell and B-cell trafficking within lymphoid organs
Although the molecular details remain to be elucidated in full, the expression of chemokines by lymph-node stroma and dendritic cells coordinates the juxtaposition of antigen-loaded dendritic cells with re-circulating T and B cells. Chemokines that may be involved in this process include DC-CK1 (CCL18), MDC (CCL22), MIP-3α, SLC and ELC.
SLC and ELC are expressed by T-zone lymph-node stroma and dendritic cells, and recruit naive T cells 20., 21.. DC-CK1 is expressed by activated mature dendritic
Effector-T-cell trafficking to sites of infection and inflammation
Thus, some activated T cells downregulate CCR7, upregulate CXCR5, become directed toward the follicle to instruct B cells in class switching and have been called ‘follicular T cells’ 24., 27.. In a Th2-polarizing environment, other T cells downregulate CCR7, upregulate CCR3, CCR4 and CCR8, and are attracted into sites of Th2 inflammation. In contrast, in a Th1-polarizing environment, certain T cells upregulate CXCR3 and CCR5, and are attracted into sites of Th1 inflammation [28].
T cells that
Chemokines link innate cells to the activation of adaptive immune cells in the tissue
Once in the tissue, Th2 cells secrete IL-4 and IL-13, and amplify Th2-cell recruitment by inducing the release of STAT6-inducible chemokines, which are active on Th2 cells. Interestingly, many of these same chemokines are also active on eosinophils, basophils and mast cells. In this way, Th2 cells control the trafficking of eosinophils, basophils and perhaps mast cells into sites of allergic inflammation (Fig. 4). Thus, activation of adaptive immune cells in the tissue leads to the production
Conclusions
Chemokines are essential for the trafficking of immune effector cells to sites of infection, and it is becoming increasingly clear that their function is necessary to translate an innate immune response into an acquired response. Innate immune stimuli—through activation of TLRs— set in motion a genetic program that induces the expression of a subset of chemokines from resident tissue macrophages and dendritic cells, and modulates the expression of chemokine receptors on dendritic cells.
These
Acknowledgements
My work is supported by grants from the National Institutes of Health. I thank Fumi Hayashi and Terry Means for their comments on the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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