SPECIALSECTION and melanoma differentiation factor 5 (MDA5) REVIEW recognize viral RNA through their helicase do- main and signal through their caspase recruitment domains (7, 8). RLRs use a common adaptor Regulation of Adaptive Immunity by the molecule mitochondria antiviral signaling protein (MAVS) (9). Engagement of MAVS by RLRs Innate Immune System leads to the activation of transcription factors nuclear factor kB(NF-kB) and interferon regulatory ′ – Akiko Iwasaki1* and Ruslan Medzhitov1,2* factor 3 (IRF3). RIG-I recognizes 5 triphosphate ssRNA with a dsRNA component: PAMPs as- sociated with many ssRNA viruses (8). Similar Twenty years after the proposal that pattern recognition receptors detect invasion by microbial RNA species are also generated by RNA poly- pathogens, the field of immunology has witnessed several discoveries that have elucidated merase III (Pol III) in the cytosol upon tran- receptors and signaling pathways of microbial recognition systems and how they control the scription of poly dA-dT–rich dsDNA (10, 11). generation of T and B lymphocyte–mediated immune responses. However, there are still many Thus, RIG-I is a sensor for both ssRNA viruses fundamental questions that remain poorly understood, even though sometimes the answers are and some dsDNA viruses (via Pol III). MDA5 assumed to be known. Here, we discuss some of these questions, including the mechanisms by preferentially recognizes long dsRNA structures which pathogen-specific innate immune recognition activates antigen-specific adaptive immune in the cytosol, a PAMP associated with positive responses and the roles of different types of innate immune recognition in host defense from ssRNA virus infections (9). infection and injury. NLRs represent a large family of intracellu- lar sensors that can detect pathogens and stress etazoans are transiently or constitu- unresolved, and new questions have arisen as a signals (12). NLRs are multidomain proteins that tively colonized by a variety of micro- result of recent progress. Here we will discuss contain a C-terminal leucine-rich repeat domain, Morganisms that can engage in mutualistic some of these emerging questions in the con- a central nucleotide-binding oligomerization or antagonistic interactions with their hosts. The text of the current knowledge of innate immune domain (NOD), and an N-terminal effector do- nature of these interactions is still poorly under- recognition. main (13). They can be divided into three sub- stood, although recent studies have begun to elu- families depending on their N-terminal domains. cidate the host receptors and signaling pathways Are All PRRs Created Equal? NLR family members detect (in most cases in- involved in sensing both commensal and patho- Microbial pathogens are recognized through directly) degradation products of peptidoglycans, genic microbes. These microbial sensing path- multiple, distinct PRRs that can be broadly various forms of stress (for instance, ultraviolet ways are used by the immune system to maintain categorized into secreted, transmembrane, and irradiation), microbial products, and noninfectious host-microbial homeostasis and to induce anti- cytosolic classes. Secreted PRRs (including col- crystal particles (12). microbial defense mechanisms. In vertebrates, lectins, ficolins, and pentraxins) bind to micro- Most, if not all, PRRs that activate the tran- two types of immunity are used to protect the bial cell surfaces, activate classical and lectin scription factors NF-kB, IRF, or nuclear factor of host from infections: innate and adaptive. The pathways of the complement system, and op- activated T cells (NFAT) are sufficient to induce innate immune system is genetically programmed sonize pathogens for phagocytosis by macro- both T and B cell responses, whereas secreted to detect invariant features of invading microbes. phages and neutrophils. PRRs and some endocytic PRRs (scavenger re- Innate immune cells include dendritic cells (DCs), The transmembrane PRRs include the Toll- ceptors and mannose receptors) cannot induce macrophages, and neutrophils, among others. In like receptor (TLR) family and the C-type lectins. adaptive immunity by themselves (14). TLRs are contrast, the adaptive immune system, which is TLRs in mammals are either expressed on the the best characterized receptors that can trigger composed of T and B lymphocytes, employs an- plasma membrane or in endosomal/lysosomal activation of adaptive immune responses of sev- tigen receptors that are not encoded in the germ organelles (2). Cell-surface TLRs recognize con- eral effector classes, including immunoglobulin line but are generated de novo in each organism. served microbial patterns that are accessible on M (IgM), IgG, and IgA antibody responses; T + Thus, adaptive immune responses are highly spe- the cell surface, such as lipopolysaccharide (LPS) helper cell 1 (TH1) and TH17 CD4 T cell re- cific. The best-characterized microbial sensors of Gram-negative bacteria (TLR4), lipoteichoic sponses; and CD8+ T cell responses (3). In a path- are the so-called pattern recognition receptors acids of Gram-positive bacteria and bacterial lipo- ological setting, TLR4 can also induce TH2and (PRRs) of the innate immune system, which de- proteins (TLR1/TLR2 and TLR2/TLR6), and IgE responses, although the functional importance tect relatively invariant molecular patterns found flagellin (TLR5), whereas endosomal TLRs of this pathway in protective immunity is current- in most microorganisms of a given class (1). mainly detect microbial nucleic acids, such as ly unknown. Engagement of dectin-1 and -2 can These structures are referred to as pathogen- double-stranded RNA (dsRNA) (TLR3), single- drive TH17 responses, which are required to clear associated molecular patterns (PAMPs), though stranded RNA (ssRNA) (TLR7), and dsDNA fungal infections (4). Several recent studies have they are not unique to microbes that can cause (TLR9). Expression of TLRs is cell-type specific, demonstrated that cytosolic PRRs, including RLRs a disease. Several families of PRRs have been allowing allocation of recognition responsibilities and some NLRs, can also activate adaptive im- characterized over the past decade, thus eluci- to various cell types (3). Dectin-1 and -2 are trans- munity (15–19). A cytosolic DNA sensor pathway dating the basic mechanisms of sensing micro- membrane receptors of the C-type lectin family is also sufficient for activation of TH1, cytotoxic bial infections; however, several questions remain that detect b-glucans and mannan, respectively, CD8+ T cell, and antibody responses through on fungal cell walls (4, 5). TANK-binding kinase-1 (20). 1Department of Immunobiology, School of Medicine, Yale The cytosolic PRRs include the retinoic acid– The relative contribution of different PRRs to 2 University, New Haven, CT 06520, USA. Howard Hughes inducible gene I (RIG-I)–like receptors (RLRs) activation of specific arms of adaptive immune Medical Institute, School of Medicine, Yale University, New Haven, CT 06520, USA. and the nucleotide-binding domain and leucine- response during microbial infections is not fully – *To whom correspondence should be addressed. E-mail: rich repeat containing receptors (NLRs). RLRs understood. Somewhat surprisingly, inflamma- [email protected] (A.I.); [email protected] detect viral pathogens (6). Unlike TLRs, most somes, rather than signaling through the viral sen- (R.M.) cell types express RLRs. RLR members RIG-I sors RLRs, are required for adaptive immunity www.sciencemag.org SCIENCE VOL 327 15 JANUARY 2010 291 Innate Immunity against influenza infection (21, 22). Similarly, pathogens, especially by viruses. In contrast, in the same endosome. This normally would infection with respiratory syncytial virus (RSV) cell-extrinsic recognition is mainly mediated by require a large excess of PAMP over what is activates MAVS-dependent antiviral innate host specialized cells of the immune system, such as minimally required for activation of DCs. The defenses, and yet, mice deficient in both MAVS macrophages and DCs. Although both types of co-recognition, however, is strongly facilitated and MyD88 (and adaptors used by most TLRs) recognition can induce antimicrobial effectors by some adjuvants, such as mineral oil and alum, can mount adaptive immune responses and clear upon activation, they may trigger adaptive immu- that promote antigen persistence and the co- RSV infection (23). Protective immunity to RSV nity by different mechanisms, as discussed in recognition of the antigen and a PAMP. This was instead shown to depend on the NLR NOD2 more detail below. effect of adjuvants can be substituted for by a (24). For many microbial infections, including The principal distinction is the way the ori- physical association of an antigen and a PAMP, the well-studied pathogens Mycobacterium tuber- gin of antigens is established by cell-extrinsic either by direct conjugation or by coabsorption culosis and Listeria monocytogenes, the rele- and -intrinsic innate immune recognition. In the on the same particles, because in both cases they vant innate immune recognition pathways are former case, the detection of a microbial cell or a will localize to the same endosomes, and the im- unknown, though some obvious candidates have viral particle by, for example, a TLR expressed mune system will interpret this as an indication been excluded. Activation of pro- that the antigen is of microbial tective CD8+ T cell responses origin. Such associative recog- to L. monocytogenes