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The cells and major functional properties of cells that play important roles in the innate immune system were discussed in Chapter 2. They include the following.

1 Polymorphonuclear leukocytes (also called granulocytes)NeutrophilsEosinophilsBasophils

2 MacrophagesKupffer cells (liver)Alveolar macrophages (lung)Splenic macrophages (spleen)Peritoneal macrophages (peritoneum)Microglial cells (nervous tissue)

3 Dendritic cellsLangerhans cells (skin)Follicular dendritic cells (follicles in spleen and lymph nodes)Interdigitating cells (thymus)Plasmacystoid cells (blood and peripheral lymphoid organs)

4 NKT cells (members of the TH cell population)

5 Innate lymphoid cells (ILCs)Group 1 ILC (NK cells)Group 2 ILCGroup 3 ILC

Innate lymphoid cells constitute a heterogeneous family of innate immune cells that have been shown to aid in protective immunity at the acute phase of infections, tissue remodeling, anatomical containment of commensals microorganisms (e.g., microbiota that inhabit our gastrointestinal tract in a symbiotic relationship in which one species is benefited while the other is unaffected), wound healing, and in maintaining the epithelial integrity at mucosal sites. ILCs have also been associated with pathophysiological conditions, such as airway and gut inflammation.

As discussed in Chapter 2, ILCs are divided into three functionally distinct groups (ILC1, ILC2, and ILC3) based upon the cytokines they produce (Figure 3.2; see also Table 2.1). The first ILCs to be characterized were those defined as natural killer (NK) cells which, as their name implies, are cells functionally programmed to kill certain cells. Altered features of the membranes of abnormal cells, such as those found on virus‐infected or cancer cells, are recognized by NK cells, which are cytotoxic. NK cells probably play a role in the early stages of viral infection or tumorigenesis, before the large numbers of activated cytotoxic T lymphocytes are generated. Histologically, NK cells are large granular lymphocytes. The intracellular granules contain preformed biologically potent molecules that are released when NK cells make contact with target cells. Some of these molecules cause the formation of pores in the membrane of the target cell, leading to its lysis. Other molecules enter the target cell and cause apoptosis (programmed cell death) of the target cell by enhanced fragmentation of its nuclear DNA. Hence, they are able to lyse certain virus‐infected cells and tumor cells without prior stimulation.

Figure 3.2. Innate lymphoid cells. ILCs are derived from precursor cells that express a transcription factor (ID2) inhibits B and T cell differentiation allowing for ILC subset‐specific transcription factors to function. ILCs are currently divided into three groups with functional properties believed to contribute to early defense responses and inflammatory diseases. They produce many of the same cytokines made by T cells but lack TCRs.

Unlike cytotoxic T lymphocytes, which recognize target cells in an antigen‐specific fashion due to their expression of T cell receptors (TCRs), NK cells lack antigen‐specific receptors. How, then, do they seek and destroy their targets? By using a mechanism involving cell–cell contact, which allows them to determine whether a potential target cell has lost a particular self‐antigen, namely major histocompatibility complex (MHC) class I. MHC class I is expressed on virtually all nucleated cells. NK cells express receptors called killer‐cell inhibitory receptors (KIR), which bind to MHC class I molecules expressed on normal cells. When ligated, KIRs inhibit downstream events that would otherwise cause the NK cell to be activated, causing degranulation and destruction of the target cells. Virus‐infected or transformed (tumor) cells have significantly reduced numbers of MHC class I molecules on their surfaces. Thus, when such cells encounter NK cells, they fail to effectively engage KIRs and therefore become susceptible to NK cell‐mediated cytotoxicity (Figure 3.3).

From this brief outline, it can be seen that each of these cellular components of the innate immune system has diverse roles that serve the host’s initial attempt to eliminate foreign substances and pathogens to the generation of antigen‐specific adaptive immune responses that ultimately give rise to long‐term immunity. Finally, as producers of an array of cytokines, soluble mediators of immune responses (see Chapter 11), these cells influence the functional properties of many other cell types within the immune system. For example, they can enhance the phagocytic activity of macrophages to increase their killing of pathogens, as well as the cytotoxic effects of NK cells. Thus, innate immune cells are pivotal players in strategies employed by the immune system to ensure protection of the host against infectious microorganisms. They are also called into play whenever physical barriers of defense are compromised (e.g., skin wounds). In either case, mobilization of innate immune cells following injury or infection generates a physiological response known as inflammation. This is discussed in more detail in the section that follows.

Figure 3.3. NK cell inhibitory receptors and killing.