Innate cell communication kick-starts pathogen-specific immunity

Abstract

Innate cells are responsible for the rapid recognition of infection and mediate essential mechanisms of pathogen elimination, and also facilitate adaptive immune responses. We review here the numerous intricate interactions among innate cells that initiate protective immunity. The efficient eradication of pathogens depends on the coordinated actions of multiple cells, including innate cells and epithelial cells. Rather than acting as isolated effector cells, innate cells are in constant communication with other responding cells of the immune system, locally and distally. These interactions are critically important for the efficient control of primary infections as well for the development of 'trained' innate cells that facilitate the rapid elimination of homologous or heterologous infections.

Figure 1

Factors that shape the type of immune response elicited by infection. The entry of pathogens into mucosal surfaces can cause damage to epithelial cells and result in the release of DAMPs. The presence of an invading pathogen is also sensed by cell-surface and cytoplasmic PRRs that detect an array of MAMPs, as well as DAMPs. PRR signaling promotes the differential induction of cytokines by epithelial cells and cells of the innate immune system. Although helminth-specific pathogen-associated molecular patterns are yet to be well characterized, worm-specific excretory and secretory products are sensed by innate cells and contribute to the overall inflammatory milieu. The effector functions of innate cells such as neutrophils and macrophages are activated differentially by the aggregate contributions of DAMPs, pathogen-associated molecular patterns and cytokines, which lead to a tailored immune response for the efficient eradication of pathogens. In the context of type 1 responses, the early induction of IL-12 and IFN-γ induces the activation of M1 macrophages with optimal capacity to contain intracellular pathogens. Similarly, neutrophils activated in a type 1 cytokine milieu acquire a tailored N1 phenotype. In contrast, infection with helminth parasites and the associated tissue damage that they cause promote a distinct inflammatory response that facilitates the differentiation of M2 macrophages and N2 neutrophils. DC, dendritic cell.

Figure 2

Local and distal intercellular communication. The entry of pathogens into diverse tissues triggers the production of tissue-derived signals that include cytokines, chemokines and alarmins. These factors can be sensed locally by innate cells as well as remotely in the bone marrow (BM), where a distal response by innate cells is initiated. In a type 1 innate response, dendritic cells secrete IL-12 and thus induce IFN-γ production by NK cells. Monocyte precursor cells can be primed by this inflammatory response in the bone marrow and enter the infected tissue in a ‘pre-educated’ state. In the infected tissue, monocyte-derived macrophages (mo-MΦ) provide important cues to tissue-resident macrophage (TR MΦ) populations to promote the production of chemokines for the recruitment of other innate cells. Tissue-resident macrophages also engage in communication with epithelial cells, including the secretion of SOCS proteins that help maintain a balanced immune response. Epithelial cells, in turn, are an important source of alarmins and cytokines that shape the response of macrophages and other recruited innate cells, such as neutrophils. Neutrophils shape the responses of other innate cells, including NK cells, and can be a source of regulatory cytokines such as IL-10, as well as ‘instructive’ cytokines such as IL-1, IL-18, IL-17 and tumor-necrosis factor (TNF). During a type 2 response, similar innate cells interact to orchestrate protection and are activated differentially to produce factors that promote type 2 immunity. Epithelial cells are an important source of DAMPs such as adenosine that trigger release of cytokine alarmins, which then drive the production of type 2 cytokines by cells of the innate immune system. Epithelial cells can also release chitinase-like proteins, which drive the secretion of IL-17 by γδ T cells. IL-17 can recruit neutrophils and potentially enhance their production of type 2 cytokines. Thus, interactions among epithelial and innate cells operate locally and distally to coordinate the elicitation of a balanced, protective inflammatory response. NETs, neutrophil extracellular traps.

Figure 3

Factors that shape trained immunity. A primary exposure to infection can ‘instruct’ the formation of trained populations of innate cells that provide enhanced protection upon secondary challenge with the same pathogen (homologous protection) or a different type of pathogen (heterologous protection). Epigenetic modifications in macrophages may form the basis of this innate memory response, although it is possible that post-transcriptional mechanisms are also important. Triggering of PRRs on responding macrophages is crucial for the induction of epigenetic changes in the trained cell. PRRs can be activated by diverse MAMPs, as well as by endogenous DAMPs released by damaged cells. Important DAMPs in this process include adenosine (ATP), TFF2 and chitinase-like proteins. It is likely that the training of innate cells is also the result of the integration of immunological signals provided by the interactions with other innate cells. The structure presented here for TFF2 is that of the representative trefoil motif–containing protein PSP (‘pancreatic spasmolytic polypeptide’; PDB accession code 2PSP); the representative chitinase-like protein structure presented here is that of Ym1 (PDB accession code 1E9L).

Figure 4

Intercellular communication orchestrates effector function and protective immunity. Various cell populations of the innate immune system engage in crosstalk with macrophages. Macrophages are crucial effectors for the defense against many pathogens. These cells can be activated differentially upon infection with diverse infectious agents. The acquisition of effector responses is tailored to each pathogen and is critically shaped by the interactions of macrophages with other innate cells and epithelial cells. Myeloid and lymphoid innate cells can differentially produce cytokines that ‘instruct’ the activation of macrophages. Effector macrophages can be derived from monocyte precursors as well as from embryonic, tissue-derived macrophages. Tissue-derived cues provided by epithelial cells are also critical for the ‘instruction’ of effective macrophage effector cells. Macrophages are also an important source of secreted factors that act on the surrounding cell populations of the immune system and help orchestrate a productive response for pathogen eradication and tissue repair. BETs, basophil-derived extracellular traps; TSLP, thymic stromal lymphopoietin.