Old Meets New: The Interaction Between Innate and Adaptive Immunity
2005; Elsevier BV; Volume: 125; Issue: 4 Linguagem: Inglês
10.1111/j.0022-202x.2005.23856.x
ISSN1523-1747
AutoresRachael A. Clark, Thomas S. Kupper,
Tópico(s)Immune Cell Function and Interaction
ResumoThe innate immune system is an ancient and diverse collection of defenses, including the recognition of pathogens through the use of germline-encoded pathogen receptors. The adaptive immune system, encompassing T and B cell responses, is a more recent development that utilizes somatically recombined antigen receptor genes to recognize virtually any antigen. The adaptive immune system has the advantage of flexibility and immunologic memory but it is completely dependent upon elements of the innate immune system for the initiation and direction of responses. Appropriate innate and acquired immune system interactions lead to highly efficient recognition and clearance of pathogens, but maladaptive interactions between these two systems can result in harmful immunologic responses including allergy, autoimmunity, and allograft rejection. The innate immune system is an ancient and diverse collection of defenses, including the recognition of pathogens through the use of germline-encoded pathogen receptors. The adaptive immune system, encompassing T and B cell responses, is a more recent development that utilizes somatically recombined antigen receptor genes to recognize virtually any antigen. The adaptive immune system has the advantage of flexibility and immunologic memory but it is completely dependent upon elements of the innate immune system for the initiation and direction of responses. Appropriate innate and acquired immune system interactions lead to highly efficient recognition and clearance of pathogens, but maladaptive interactions between these two systems can result in harmful immunologic responses including allergy, autoimmunity, and allograft rejection. immunoglobulin interleukin pathogen-associated molecular patterns Toll-like receptors T-regulatory Immunologic defenses in vertebrates consist of two immunologic subsystems—innate and adaptive. For much of the past 30 years, immunologists and microbiologists have studied innate and adaptive immunity in isolation. Today, these elements of immunity are appreciated as obligate and synergistic parts of the system that mediate successful host responses to infection and tissue injury. The innate immune system encompasses a collection of host defenses that range from the non-specific barrier function of epithelia to the highly selective recognition of pathogens through the use of germline-encoded receptors. A common feature of these diverse elements is a rapid and blunt response to infection or tissue destruction (Janeway and Medzhitov, 2002Janeway Jr, C.A. Medzhitov R. Innate immune recognition.Annu Rev Immunol. 2002; 20: 197-216Google Scholar). In contrast, the adaptive immune system uses somatically rearranged antigen receptor genes to create receptors for virtually any antigen. The adaptive immune response is slower but more flexible and is able to combat infections that have evolved to evade innate responses. The adaptive immune system has the capacity to recognize and respond to virtually any protein or carbohydrate imaginable; yet, without the innate immune system to instruct it—in effect, telling it whether, when, how, and where to respond—it is powerless. The mechanisms by which the innate immune system instructs and directs adaptive immune responses are becoming increasingly clear and what follows is a discussion of this immunologic interface. The innate immune system responds by recognition of conserved motifs in pathogens as well as a number of other indicators of cell stress or death. The cellular components of the innate immune system include dendritic cells, monocytes, macrophages, granulocytes, and natural killer T cells, as well as the skin, pulmonary, and gut epithelial cells that form the interface between an organism and its environment. The non-cellular aspects of the innate system are diverse and range, from the simple barrier function of the stratum corneum to complex pathways such as the complement cascade. These non-cellular elements seek to prevent the entry of pathogens through physical blockade, or once invaded, to destroy pathogens directly or call them to the attention of phagocytes. This review will focus primarily on innate immune elements that are known to interface with the adaptive immune system. The innate immune system has evolved to recognize molecular patterns common to many classes of pathogens; these elements have been termed pathogen-associated molecular patterns (PAMP). PAMP are diverse and include lipopolysaccharides (LPS), aldehyde-derivatized proteins, mannans, teichoic acids, denatured DNA, and bacterial DNA (Medzhitov and Janeway, 2002Medzhitov R. Janeway Jr, C.A. Decoding the patterns of self and nonself by the innate immune system.Science. 2002; 296: 298-300Google Scholar). The innate immune system recognizes PAMP using a group of germline-coded, evolutionary conserved proteins termed pathogen-recognition receptors (PRR) (Janeway and Medzhitov, 2002Janeway Jr, C.A. Medzhitov R. Innate immune recognition.Annu Rev Immunol. 2002; 20: 197-216Google Scholar). PRR were initially defined as cell-surface pathogen receptors present on innate immune cells, but this definition has been expanded to include secreted and locally produced molecules that mediate many steps in inflammation including directed phagocytosis, activation of inflammatory signaling pathways, induction of cell death, and activation of the complement or coagulation cascades (Janeway and Medzhitov, 2002Janeway Jr, C.A. Medzhitov R. Innate immune recognition.Annu Rev Immunol. 2002; 20: 197-216Google Scholar). The Toll-like receptors (TLR) are a particularly important group of pathogen receptors. These molecules are expressed on both innate immune cells and on cells in various tissues including endothelial cells, epithelial cells, and fibroblasts (Schnare et al., 2001Schnare M. Barton G.M. Holt A.C. et al.Toll-like receptors control activation of adaptive immune responses.Nat Immunol. 2001; 2: 947-950Google Scholar; Janeway and Medzhitov, 2002Janeway Jr, C.A. Medzhitov R. Innate immune recognition.Annu Rev Immunol. 2002; 20: 197-216Google Scholar). Ten TLR family members specific for various microbial molecules have been identified in humans. Binding of TLR to their microbial ligands leads to activation of phagocytes and direct killing of pathogens, as well as to the release of pro-inflammatory cytokines and anti-microbial peptides (Takeda et al., 2003Takeda K. Kaisho T. Akira S. Toll-like receptors.Annu Rev Immunol. 2003; 21: 335-376Google Scholar). In addition, these molecules activate dendritic cells and are therefore important in the initiation of adaptive immune responses, a role that will be discussed more fully below. Binding of ligands to TLR triggers activation of the nuclear factor-κB (NF-κB) signaling pathway (Takeda et al., 2003Takeda K. Kaisho T. Akira S. Toll-like receptors.Annu Rev Immunol. 2003; 21: 335-376Google Scholar). This signaling pathway is a master switch for the induction of inflammation. In the skin, NF-κB signaling induces the expression of chemokines, cytokines, adhesion molecules, matrix metalloproteases, nitric oxide synthase, and enzymes that regulate prostanoid synthesis, in short, everything needed to instigate an inflammatory response (Medzhitov and Janeway, 1997Medzhitov R. Janeway Jr, C.A. Innate immunity: The virtues of a nonclonal system of recognition.Cell. 1997; 91: 295-298Google Scholar). In addition to TLR, other types of tissue factors associated with inflammation can act as danger signals leading to the activation of phagocytes and dendritic cells (Matzinger, 2002Matzinger P. The danger model: A renewed sense of self.Science. 2002; 296: 301-305Google Scholar; Kapsenberg, 2003Kapsenberg M.L. Dendritic-cell control of pathogen-driven T-cell polarization.Nat Rev Immunol. 2003; 3: 984-993Google Scholar). These factors include heat-shock proteins, lectins, cytokines, chemokines, extracellular matrix components, and various cell-surface molecules including lipids from necrotic cells. These danger signals lead to phagocyte activation and destruction of endocytosed pathogens as well as activation of dendritic cells and the resultant initiation of adaptive immune responses. Anti-microbial proteins and peptides are additional components of the innate immune system. These molecules include large proteins such as lysozyme and cathepsin G as well as smaller anti-microbial peptides including the defensins, cathelicidins, and the skin anti-microbials dermcidin and psoriasin (Madsen et al., 1991Madsen P. Rasmussen H.H. Leffers H. et al.Molecular cloning, occurrence, and expression of a novel partially secreted protein "psoriasin" that is highly up-regulated in psoriatic skin.J Invest Dermatol. 1991; 97: 701-712Google Scholar; Schittek et al., 2001Schittek B. Hipfel R. Sauer B. et al.Dermcidin: A novel human antibiotic peptide secreted by sweat glands.Nat Immunol. 2001; 2: 1133-1137Google Scholar; Ganz, 2003Ganz T. Defensins: Antimicrobial peptides of innate immunity.Nat Rev Immunol. 2003; 3: 710-720Google Scholar). Mice deficient for cathelicidin are susceptible to infections with Group A Streptococcus, demonstrating the importance of these molecules (Nizet et al., 2001Nizet V. Ohtake T. Lauth X. et al.Innate antimicrobial peptide protects the skin from invasive bacterial infection.Nature. 2001; 414: 454-457Google Scholar). The defensin family of peptides has anti-microbial effects at physiologic concentrations and is produced by a variety of cell types including neutrophils and epithelial cells of the epidermis, bronchial tree, and genitourinary tract. Defensins kill pathogens directly through cell lysis and can also induce the chemotaxis of monocytes, dendritic cells, and T cells. For example, the defensin hBD-2 binds to the CCR6 chemokine receptor and is chemotactic for both immature dendritic cells and memory T cells (Yang et al., 1999Yang D. Chertov O. Bykovskaia S.N. et al.Beta-defensins: Linking innate and adaptive immunity through dendritic and T cell CCR6.Science. 1999; 286: 525-528Google Scholar). This is a notable example of a molecule, microbicidal in its own right, that also signals to key elements of both the innate and adaptive immune systems. Anti-microbial peptides have particular clinical relevance in dermatology. It has long been observed that patients with psoriasis, a chronic inflammatory and hyperproliferative skin disorder, suffer from fewer skin infections than would be expected, given the degree of skin barrier disruption. It was recently reported that psoriatic scales contain high levels of anti-microbial peptides including defensins, psoriasin, and additional novel compounds (Harder and Schroder, 2005Harder J. Schroder J.M. Psoriatic scales: A promising source for the isolation of human skin-derived antimicrobial proteins.J Leukoc Biol. 2005; 77: 476-486Google Scholar). The anti-microbial psoriasin, first isolated from psoriatic epidermis (Madsen et al., 1991Madsen P. Rasmussen H.H. Leffers H. et al.Molecular cloning, occurrence, and expression of a novel partially secreted protein "psoriasin" that is highly up-regulated in psoriatic skin.J Invest Dermatol. 1991; 97: 701-712Google Scholar), protects human skin from Escherichia coli infection (Glaser et al., 2005Glaser R. Harder J. Lange H. et al.Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.Nat Immunol. 2005; 6: 57-64Google Scholar). The high levels of microbicidal peptides in psoriatic skin may underlie its relative resistance to bacterial superinfection. In contrast, skin affected by atopic dermatitis is notoriously susceptible to infections with Gram-positive bacteria and has also been found to lack expression of the important anti-microbial proteins cathelicidin and the defensin hBD-2 (Ong et al., 2002Ong P.Y. Ohtake T. Brandt C. et al.Endogenous antimicrobial peptides and skin infections in atopic dermatitis.N Engl J Med. 2002; 347: 1151-1160Google Scholar). T and B lymphocytes are the cellular elements of the adaptive immune system, a relatively recent evolutionary development dating back to the emergence of vertebrates some 400 million years ago. The hallmarks of the adaptive immune response are flexibility and memory. Flexibility is provided by the unique way in which T and B cells recognize antigens. Unlike cells in the innate system, which use a fixed repertoire of inherited receptors, T and B cells undergo a recombination of antigen receptor genes to create novel and unique antigen receptors capable of recognizing virtually any antigen. B and T cells that have encountered antigen persist over the long term within an organism and provide rapid and specific responses to reinfection, a concept known as immunologic memory. Antibodies, encoded by heavy and light immunoglobulin (Ig) genes, are the antigen receptors on B cells. Antibodies can be both cell surface bound and secreted and are classified by the isotype of their heavy chains (IgM, IgG, IgE, IgA). Antibodies recognize the tertiary (three dimensional) structure of native proteins and glycoproteins. B cells first produce pentameric IgM but under the influence of T cell cytokines and other factors, B cells undergo additional genetic recombination events leading to isotype switching and production of IgG subtypes, IgE or IgA. Fine tuning of antigen specificity is also accomplished by affinity maturation. This process involves hypermutation of antibody genes combined with competition for antigen within lymphoid follicles, leading to selective survival of B cells with the highest affinity for antigen. T cell receptors differ from B cell receptors in several fundamental ways. First, they are never secreted, existing instead on the cell surface as heterodimers of αβ or γδ subunits. Second, T cells recognize peptides produced by the proteolytic cleavage of antigens as opposed to the native proteins recognized by B cells. Thus, T cells recognize the primary structure (amino acid sequence), and B cells recognize the tertiary (three-dimensional folded) structure of a protein. Lastly, T cells recognize antigenic peptides only when they are presented on the cell surface bound to class I or class II major histocompatibility (MHC) proteins. Cellular cross-talk is a hallmark of the adaptive immune system. In order for naïve B cells to proliferate and differentiate in response to most antigens, they must be stimulated by a CD4+ helper T cell that is specific for the same antigen. T cells also require a second signal in order to proliferate and differentiate after encountering antigen. T cells that do not receive this co-signal are likely to be rendered unresponsive, or anergic. Thus, T cells determine what B cell antigens will be recognized, and T cells need another signal in order to proliferate in response to antigen, a signal that can be provided by B cells. B and T cells therefore engage in a complex dialog during immune responses. T cells can be divided into a number of distinctive subsets based on their migration patterns and functional abilities. Naïve T cells recirculate primarily between the blood and lymph nodes, a pattern aided by their expression of the homing receptors L-selectin and CCR7 (Mackay et al., 1990Mackay C. Marston W. Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation.J Exp Med. 1990; 171: 801-817Google Scholar; Sallusto et al., 1999Sallusto F. Lenig D. Forster R. Lipp M. Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.Nature. 1999; 401: 708-712Google Scholar). This allows them to sample the environments of lymph nodes from different tissue types, increasing their chances of encountering specific antigen. Memory T cells can be further divided into central memory and effector memory cells (Sallusto et al., 2004Sallusto F. Geginat J. Lanzavecchia A. Central memory and effector memory T cell subsets: Function, generation, and maintenance.Annu Rev Immunol. 2004; 22: 745-763Google Scholar). Central memory T cells primarily migrate between blood and lymph nodes in a pattern similar to that of naïve T cells, although recent evidence suggests that these cells may also enter peripheral tissues (Campbell et al., 2001Campbell J.J. Murphy K.E. Kunkel E.J. et al.CCR7 expression and memory T cell diversity in humans.J Immunol. 2001; 166: 877-884Google Scholar). Central memory T cells serve primarily as long-lived reservoirs of immunologic memory. When stimulated with antigen, these cells give rise to additional central memory cells as well as effector memory T cells. Effector memory T cells are shorter lived and aggressive, specialized for migration into target tissues and neutralization of pathogens (Sallusto et al., 2004Sallusto F. Geginat J. Lanzavecchia A. Central memory and effector memory T cell subsets: Function, generation, and maintenance.Annu Rev Immunol. 2004; 22: 745-763Google Scholar). Memory T cells can also be characterized based on what peripheral tissues they enter. The body can be subdivided into different immunologic zones, and T cells that encounter antigen first in a particular tissue tend to recirculate through that tissue in the future (Campbell and Butcher, 2002Campbell D.J. Butcher E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues.J Exp Med. 2002; 195: 135-141Google Scholar; Kupper and Fuhlbrigge, 2004Kupper T.S. Fuhlbrigge R.C. Immune surveillance in the skin: Mechanisms and clinical consequences.Nat Rev Immunol. 2004; 4: 211-222Google Scholar). This tissue-specific migration is controlled by the expression of specific molecules, termed homing receptors, on the surface of memory T cells. Expression of the homing receptor cutaneous lymphocyte antigen guides T cells to the skin, and expression of the integrin α4β7 sends T cells specifically to the gut (Picker et al., 1990Picker L.J. Michie S.A. Rott L.S. Butcher E.C. A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites.Am J Pathol. 1990; 136: 1053-1068Google Scholar; Butcher et al., 1999Butcher E.C. Williams M. Youngman K. Rott L. Briskin M. Lymphocyte trafficking and regional immunity.Adv Immunol. 1999; 72: 209-253Google Scholar). This selective recirculation to the sites of prior antigen exposure allows T cells to focus their attention on sites where this antigen is most likely to be encountered in the future. Lastly, CD4+ T helper cells can be functionally divided into Th1-, Th2-, and T-regulatory (Treg) cells. Th1 cells secrete Th1 cytokines including IFN-γ and TNF-β and are efficient at activating macrophages and stimulating cytotoxic T cells, thereby inducing what is termed cell-mediated immunity. Th2 T cells secrete Th2 cytokines such as interleukin (IL)-4, IL-5, and IL-13, and are efficient at stimulating B cells to make antibodies, in particular IgE, inducing what is called the humoral immune response (Mosmann and Coffman, 1989Mosmann T.R. Coffman R.L. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties.Annu Rev Immunol. 1989; 7: 145-173Google Scholar). The immune response to a pathogen can be primarily cellular or humoral, based on the particular response of an individual. In general, Th1 cytokines encourage cellular immunity and can suppress Th2 responses. A notable exception is the finding that the Th1 cytokine IFN-γ acts to induce B cell production of IgG2a antibodies, a subtype implicated in Th2 autoimmune diseases including lupus (Gavalchin et al., 1987Gavalchin J. Seder R.A. Datta S.K. The NZB X SWR model of lupus nephritis. I. Cross-reactive idiotypes of monoclonal anti-DNA antibodies in relation to antigenic specificity, charge, and allotype. Identification of interconnected idiotype families inherited from the normal SWR and the autoimmune NZB parents.J Immunol. 1987; 138: 128-137Google Scholar; Snapper and Paul, 1987Snapper C.M. Paul W.E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production.Science. 1987; 236: 944-947Google Scholar). Similarly, Th2 cytokines activate humoral responses and can act to suppress cellular responses. Treg cells are a recently recognized family of CD4+ T cells that act to suppress the responses of other T cells. These cells play a role in regulating self-tolerance but may also interfere with immunity to tumors (Sakaguchi et al., 2001Sakaguchi S. Sakaguchi N. Shimizu J. et al.Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: Their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance.Immunol Rev. 2001; 182: 18-32Google Scholar). In summary, T cells can be considered to be "polarized" in a number of different ways. Memory T cells are spatially polarized in that they migrate to specific tissues based on where they first encountered antigen. Secondly, helper T cells are functionally polarized in that they encourage different types of immunity: cellular immunity, humoral immunity, or no immunity (tolerance). Lastly, memory T cells are both spatially and functionally polarized by whether they migrate primarily to lymph nodes and promote memory responses (central memory T cells) or migrate to peripheral tissues and promote destruction of pathogens (effector memory T cells). These T cell polarization states help to fine tune and regulate the adaptive immune response. Most, if not all, of these polarization states are the direct result of signaling from the innate immune system through its intermediate cell, the dendritic cell. Dendritic cells are members of the innate immune system that are particularly efficient at stimulating T cells to respond to antigen (Banchereau and Steinman, 1998Banchereau J. Steinman R.M. Dendritic cells and the control of immunity.Nature. 1998; 392: 245-252Google Scholar). Dendritic cells are the only cells capable of activating naïve T cells, and they can load endocytosed antigenic peptides on both MHC class I and MHC class II molecules, allowing presentation to both CD8 and CD4 T cells (Rescigno et al., 1998Rescigno M. Citterio S. Thery C. et al.Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells.Proc Natl Acad Sci USA. 1998; 95: 5229-5234Google Scholar; Guermonprez et al., 2003Guermonprez P. Saveanu L. Kleijmeer M. et al.ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells.Nature. 2003; 425: 397-402Google Scholar). Dendritic cells develop in the bone marrow and migrate to the tissues in an immature form. Immature dendritic cells efficiently take up antigens from the environment but they do not provide T cell co-stimulatory signals and are therefore poor activators of T cells. Dendritic cells undergo maturation when they are exposed to a number of danger signals including the PAMP described above as well as various cytokines and tissue factors (Chain, 2003Chain B.M. Current issues in antigen presentation—focus on the dendritic cell.Immunol Lett. 2003; 89: 237-241Google Scholar). Upregulation of co-stimulatory molecules occurs during maturation with the result that mature dendritic cells are extremely potent activators of T cell responses. Dendritic cells detect danger signals within the tissues and transmit this information to T cells. Pathogens and tissue insults of many kinds are translated into a common result—activation and maturation of dendritic cells through the NF-κB signaling pathway. It is now becoming recognized that dendritic cells pass on a remarkable amount of information to T cells about the type of insult that prompted their maturation (Kapsenberg, 2003Kapsenberg M.L. Dendritic-cell control of pathogen-driven T-cell polarization.Nat Rev Immunol. 2003; 3: 984-993Google Scholar). This information affects whether a T cell will respond to antigen, how it will respond, and likely where it will go to respond. The signals that mediate this rich communication are only partially established, and the discussion below will focus on what is currently known about this process. Dendritic cells provide a number of sequential signals to responding T cells. The first signal consists of the interaction of the T cell receptor with specific antigen and MHC on the surface of the dendritic cell and determines the antigen specificity of the response. The second signal provides the co-signaling that T cells need in order to respond to antigen. This co-signaling can be either positive (co-stimulation) or negative (co-inhibition) and can be provided by a growing family of molecules including CD80 (B7-1), CD86 (B7-2), CD28, and CTLA-4 (Baxter and Hodgkin, 2002Baxter A.G. Hodgkin P.D. Activation rules: The two-signal theories of immune activation.Nat Rev Immunol. 2002; 2: 439-446Google Scholar; Chen, 2004Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity.Nat Rev Immunol. 2004; 4: 336-347Google Scholar). In the absence of a second signal or in the presence of a co-inhibitory signal, T cells fail to respond to antigen and may in fact be rendered unresponsive to this antigen in the future (Figure 1a). Thus, the second signal answers the question "will I respond?" The third signal delivered by the dendritic cell stimulates CD4+ T cells to develop into Th1, Th2, or Treg T cells (Figure 1b). This third signal determines the functional polarization of these cells and answers the question "how will I respond?" Lastly, T cells receive poorly characterized signals from either dendritic cells or their environment, which stimulate them to produce homing receptors that will direct them to migrate through tissues similar to those in which they first encountered antigen (Campbell and Butcher, 2002Campbell D.J. Butcher E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues.J Exp Med. 2002; 195: 135-141Google Scholar) (Figure 1c). This fourth signal determines spatial polarization and answers the question "where do I go to respond?" As our knowledge about the complexities of lymphocyte behavior expands, additional signals that fine tune T cell responses will likely be discovered. Co-signaling (the second signal) is delivered by dendritic cells that have undergone activation and maturation in response to the detection of danger signals in the environment. These signals, described above, are diverse but generally have activation of the NF-κB pathway in common (Bonizzi and Karin, 2004Bonizzi G. Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity.Trends Immunol. 2004; 25: 280-288Google Scholar). In most cases, activation of dendritic cells leads to maturation but there are certain immunosuppressive drugs and microbial compounds that arrest dendritic cells in an immature state, preventing them from expressing co-stimulatory molecules. These dendritic cells are unable to stimulate lymphocytes fully and may in fact induce tolerance through anergy or production of Treg cells (Kapsenberg, 2003Kapsenberg M.L. Dendritic-cell control of pathogen-driven T-cell polarization.Nat Rev Immunol. 2003; 3: 984-993Google Scholar). For example, Plasmodium falciparum infects red blood cells and these infected cells paralyze dendritic cells by binding to CD36 and CD52 (Urban and Roberts, 2002Urban B.C. Roberts D.J. Malaria, monocytes, macrophages and myeloid dendritic cells: Sticking of infected erythrocytes switches off host cells.Curr Opin Immunol. 2002; 14: 458-465Google Scholar). Thus, although the innate immune system is efficient at perceiving a variety of danger signals and translating these into T cell responses via dendritic cell maturation, there are a number of pathogens that have evolved to evade this response. Functional polarization of T cells by dendritic cells (the third signal) is a remarkable story that continues to unfold. Different PAMP and danger signals appear to polarize dendritic cells functionally into Th1-, Th2-, or Treg-type cells, imprinting them with the ability to produce cytokines and to induce T cells to differentiate selectively into Th1, Th2, or Treg cells. PAMP and other danger signals can thus be divided into type 1, type 2, and regulatory-type PAMP that induce the formation of Th1, Th2, and Treg cells, respectively. Dendritic cells subsets appear to be flexible in that they can adopt any polarization state, although rare subtypes may be hardwired to produce Treg cells (Bilsborough et al., 2003Bilsborough J. George T.C. Norment A. Viney J.L. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties.Immunology. 2003; 108: 481-492Google Scholar). Thus, dendritic cells tell T cells not only to respond but also how to respond, tipping them off as to the type of immune response that should be initiated. Type 1 PAMP have been most fully studied and include many but not all of the TLR. For example, double-stranded RNA binds to the TLR3 (Alexopoulou et al., 2001Alexopoulou L. Holt A.C. Medzhitov R. Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.Nature. 2001; 413: 732-738Google Scholar) and induces the maturation of dendritic cells that strongly support the formation of Th1 T cells (Cella et al., 1999Cella M. Salio M. Sakakibara Y. et al.Maturation, activation, and protection of dendritic cells induced by double-stranded RNA.J Exp Med. 1999; 189: 821-829Google Scholar; de Jong et al., 2002de Jong E.C. Vieira P.L. Kalinski P. et al.Microbial compounds selectively induce Th1 cell-promoting or Th2 cell-promoting dendritic cells in vitro with diverse th cell-polarizing signals.J Immunol. 2002; 168: 1704-1709Google Scholar). LPS binding to TLR4 induce
Referência(s)