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Jansen, C.A. Innate Immune Cells in the Chicken Intestine. Encyclopedia. Available online: (accessed on 11 December 2023).
Jansen CA. Innate Immune Cells in the Chicken Intestine. Encyclopedia. Available at: Accessed December 11, 2023.
Jansen, Christine A.. "Innate Immune Cells in the Chicken Intestine" Encyclopedia, (accessed December 11, 2023).
Jansen, C.A.(2021, December 22). Innate Immune Cells in the Chicken Intestine. In Encyclopedia.
Jansen, Christine A.. "Innate Immune Cells in the Chicken Intestine." Encyclopedia. Web. 22 December, 2021.
Innate Immune Cells in the Chicken Intestine

The chicken intestinal epithelium is a monolayer consisting of various cell types. Intercellular junctional complexes, tight junctions, present between the intestinal epithelial cells maintain the gut barrier integrity. Tight junctions hold the intestinal epithelial cells together to prevent the entry of enteric pathogens and thus maintain gut homeostasis. In addition to the gut microbiota, also intestinal epithelial cells inhibit the entry of pathogens for example by producing a mucus layer. In addtion to this physical barreier, also soluble factors suc a antimicrobial compunds play a role in the defence against pathogens. When all these defense mechanism are not sufficient in protecting the host, the cells of the intestinal innate immune system are activated. Properties and function of these cells are the subject of this entry.

innate immune cells intestine

1. Natural Killer (NK) Cells of the Intestinal Immune System

NK cells are involved in the innate defense, they are scavenger cells and their primary function is to recognize the virally infected, transformed, and neoplastic host cells and kill them [1][2]. NK cells originate in the bone marrow and migrate towards blood and organs like the spleen, lungs, and intestine [3]. In the chicken intestine NK cells are embedded between the enterocytes as intraepithelial lymphocytes along the length of the gut. In intestinal intraepithelial lymphocytes NK cells comprise even higher numbers than CD8+ T cells and γδ T cells [4][5] suggesting an important role in the intestinal innate immune system [6].
Chicken NK cells are described as a population of cells that lack surface expression of CD3 or Ig [5] that is able to kill the NK susceptible cell line (LSCC-RP9) [4]. Based on these characteristics, many studies have reported the presence of NK cells in various tissues like spleen, lungs and intestine of chickens [7][8][9][10][11]. NK cells are also present in large numbers in the embryonic spleen and duodenum of chickens [4][8][11][12] indicating that they are indeed important in early life innate defense.
The induction of NK cell activation is mediated by an array of activating and inhibitory receptors which are present on their surface [13]. Also, in the chicken genome NK cell receptors have been reported to be present. The leucocyte receptor complex on chromosome 31 encodes for chicken Ig-like receptors (CHIR) [14]. Chromosome 1 harbors the NK gene complex which encodes NKG2/CD94 and syntenic to the mammalian NK complex region [14][15][16].
Upon crosslinking, activation receptors on NK cells signal via immunoreceptor tyrosine-based activation motifs (ITAMs) which initiates downstream signaling, while inhibitory receptors signal via immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The delicate balance between activating and inhibitory signals received by NK cell receptors activates NK cells [17][18][19].
Once activated, NK cells release lytic granules that contain perforin and granzyme to lyse target cells [20][21]. The degranulation of NK cells upon activation can be detected using the CD107 assay [8], since enhanced surface expression of CD107a, the lysosomal-associated membrane protein-1 (LAMP-1), is associated with NK cell activation [7]. In chickens, enhanced CD107 surface expression was reported on CD3 negative cells that express surface markers such as 28-4, 20E5, CD11b/c, and 7C1 suggesting that these are markers of cells with NK cell function.
NK cells that express 28-4 (the chicken IL-2Ra orthologue) are mostly present in the duodenum of layer chickens and have been shown to able to kill susceptible target cells (LSCC-RP9) [4][22]. In other organs such as spleen, blood, and lung of layer chickens NK cells expressing 28-4 are less dominant, here the major populations express 5C7 and 20E5 [4][8][22][23].
In the intestine, the majority of NK cells express 28-4, while lower expression of NK cell markers 20E5 and 5C7 was observed. The number of 28-4 expressing NK cells was higher at day 1 post-hatch compared to levels at embryonic day 14 and 18, and remained stable throughout the life. Conversely, the number of 20E5+ and 5C7+ cells was lower in 1 day-old chickens compared to embryonic day 14 and 18 and increased until day 21 post-hatch. Among intestinal NK cells, surface expression of CD107 was also higher in the 28-4+ subset as compared to intestinal 20E5+ cells suggesting that this population may play a role in the intestinal innate immune response [11].
Upon activation NK cells may also secrete the cytokine interferon-γ, which recruits and activates immune cells from peripheral blood and nearby lymphoid tissues to amplify the innate immune response against bacteria and/or viruses and to initiate adaptive immune response [24][25].

2. Heterophils of the Intestinal Immune System

Heterophils are the avian analogues of mammalian neutrophils and immediately appear at the site of infection to eliminate invasive pathogens [26][27]. Heterophils use multiple strategies such as phagocytosis, degranulation, and oxidative burst to kill the pathogens. In chickens, heterophils are the predominant granulocytes in circulating blood and the gut [28][29][30][31][32][33]. Heterophils are comparatively higher in number in young chickens as compared to the older ones [34]. However, in young birds heterophils are functionally less active as indicated by decreased phagocytosis, degranulation, oxidative burst and, subsequently, killing of bacteria.
In the chicken intestine, pro-inflammatory cytokines produced as a result of microorganism invasion attract heterophils to the site of infection [35]. Upon contact with pathogens, heterophils are activated through the interaction of TLRs with bacterial ligands such as LPS, peptidoglycan, flagellin, and lipoteichoic acid [36][37]. This activation of heterophils results in a sequence of events including phagocytosis, oxidative burst, degranulation, and cytokine (IL1β, IL6) and chemokine (CXCLi2) production through the NF-κB pathway [36][38]. Heterophils also become activated via avian triggering receptor expressed on myeloid cells-1 (TREM-A1), which modulates TLR signaling and causes phagocytosis [39].
Phagocytosis is the process by which heterophils internalize the pathogens. Following internalization, microorganisms are entrapped in a vacuole called the phagosome, which then immediately fuses with cytoplasmic granules leading to killing of entrapped pathogens by release of anti-microbicidal peptides and proteolytic enzymes from intracellular granules [40].
Degranulation is another host defense strategy used by heterophils to kill pathogens. Upon microbial agonist stimulation, heterophils release their cytoplasmic granules at the site of infection into the external environment to kill pathogens. Another important event closely linked with extracellular degranulation is the production of heterophil extracellular traps (HET) to trap pathogens. The HET is similar to the neutrophil extracellular trap [41]. This process allows heterophils to entrap and kill bacteria extracellularly. The HET mechanism is initiated by the formation of thin extracellular fibers (5–17 nm) between pathogens and heterophils [42]. This meshwork of fibers acts as a death trap and prevent the dissemination of pathogens in the tissues. Moreover, HET also destroy pathogens by highly concentrated microbicidal substances. Finally, phagocytes also use oxidative burst to produce reactive oxygen species for microbial killing. However, unlike neutrophils, avian heterophils are mostly dependent on non-oxidative killing of pathogens as they don’t generate strong oxidative burst as compared to their mammalian analogues [43][44].

3. Dendritic Cells (DCs) of the Intestinal Immune System

DCs act as an immunological bridge between innate and adaptive immunity since these cells are the key player of antigen presentation. The intestinal DCs take up and process antigens, and present these to adaptive immune cells, which initiates a pathogen-specific immune response [45]. In mice DCs are present underneath the intestinal epithelium together with macrophages [46]. Monocytes, macrophage progenitors, and DCs express colony stimulating factor 1 receptor [47]. The intestinal DCs in human and mice can be differentiated from intestinal monocyte-derived macrophages using CD64 expression [48].
Avian DCs are less well characterized compared to human and mice DCs in which the ontogeny and heterogenous nature is extensively explored [49][50][51]. Avian DCs are defined by the expression of several markers such as CD83, CD11c, DEC205, and MHC II [52][53][54][55]. In chickens, DCs expressing CD83 and DEC205 markers are particularly abundant in the spleen, cecal tonsils, thymus, and bursa of fabricius [54]. In the chicken intestine, DCs have been described in the clusters of the GALT. Follicular DCs are located in the germinal center of the cecal tonsil, and pyloric tonsils [56][57][58]. Follicular and interdigitating DCs have also been described in the PP [59].
Immature avian DCs are equipped with a variety of TLRs to recognize invading pathogen [60]. DCs also express the CCR6 chemokine receptor. Binding of of CCR6 to this receptor induces infiltration of the DCs at the infection site to encounter antigens, due to which immature DCs transform into the mature phenotype that presents antigens to T cells. Stimulation of chicken bone marrow derived DCs with LPS results into maturation of chicken DCs, which parallels increased expression of co-stimulatory molecules CD40, CD83, CD86, and a decrease in phagocytic activity [53][61]. DCs interact with LPS of the Gram-negative bacteria through TLR4, which activates CD14 dependent endocytosis of TLR4 [62]. In addition to antigen presentation, DCs also produce cytokines such as IL1β, IL6, 1L10, IL12p35, and TNFα, and CXCL chemokines to attract other immune cells and to enhance inflammatory processes [63][64].

4. Macrophages of the Intestinal Immune System

Macrophages are a type of innate immune cells, which can be involved in the defense against bacterial infections [65]. Macrophages actively recognize, phagocytize, and kill microbes by producing microbicidal substances like nitric oxide, reactive oxygen species, proteolytic enzymes, and lysozyme [66][67][68][69][70]. Upon contact with a pathogen, macrophages become activated and transform into either M1 or M2 phenotype [71][72][73]. The polarization of the macrophages into M1 or M2 phenotypes depends upon the activation pathway and the type of cytokines they are exposed to. Exposure of macrophages to intracellular bacteria and T helper cell type 1 (Th1) cytokines (interferon and TNFα) leads to M1 polarization [74], while T helper cell type 2 (Th2) cytokines (IL4, and 13) transform macrophages into the M2 phenotype [75][76][77].
Whether this polarization also occurs in chicken macrophages is currently not clear. It has been shown, in vitro, that cultured avian macrophages can have a more M1 like phenotype as described by Peng et al. [78] for monocyte-derived macrophages, while an IL4 induced polarization towards a more M2 phenotype has also been described [79]. However, evidence for the presence of M1 and M2 macrophages in vivo is still missing.
Chicken macrophages recognize pathogens by their phagocytic receptors [80], that may be opsonic (complement receptors, Fc receptors) or non-opsonic (TLRs, mannose receptors) [81][82][83][84]. Chicken intestinal macrophages possess a range of TLRs, and hence respond accordingly to a variety of bacterial ligands such as LPS, CpG oligonucleotides, and flagellin [85][86][87][88].
Upon pathogen recognition, macrophages activate intracellular signals (mitogen activated protein kinase p38) orchestrate the innate immune response by production of cytokines (TNFα, IL1, IL10), chemokines, and nitric oxide (NO) which has antibacterial properties [89][90][91][92][93][94][95][96]. In a recent study it has been shown that HD11 cells, a macrophage-like cell line, when stimulated with inactivated poultry vaccines, showed an increase in Fc-receptor driven phagocytosis as well as NO production when activated with TLR agonists [97]. In another study, HD11 cells stimulated with inactivated Avibacterium paragallinarium, led to NO production and express pro-inflammatory cytokines TNFα, IL1β, and IL12p40, as well as chemokines CXCLi1 and CXCLi2 [98].
In the chicken intestine, macrophages play a vital role in antigen presentation along with DCs, as well as act as regulators and effectors of immunity. Macrophages are present in the intestinal lamina propria in chickens and reach the invasion site after IFNγ production [99]. It has been shown that IFNγ stimulation increases the antiviral and phagocytic activity of macrophages and also induces IL12 and IL18 production which drives Th1 adaptive response [100][101].

5. γδ T Cells of the Intestinal Immune System

γδ T cells are unconventional CD3+ T cells having a unique T cell receptor (TCR) that consists of a γ chain and a δ chain. The number of γδ T cells in blood varies between 0.5 to 10% in humans, dogs, mice and monkeys [102][103], while in chickens, cattle and pigs γδ T cells ranges from 20–50% of the total circulating T cells in blood [104][105][106][107]. Apart from blood, γδ T cells have also been reported in, for example, the intestine and spleen and their frequency depends on age, sex, and strain of chickens [108][109].
The majority of the avian γδ T cells is activated in a MHC unrestricted way unlike αβ T cells [110]. Although toll-like receptors (TLR3 and 4) are present on chicken γδ T cells along with the scavenger receptor superfamily, their role in TCR independent activation of γδ T cells in chickens is still unclear [109][111]. Recently, Karunakaran et al. showed the TCR dependent activation of human γδ T cells. After stimulating γδ T cells with phospho-antigens, molecules present inside the infected cells, γδ T cells get activated to kill the target cell [112]. Activated γδ T cells also produce IL17 and IFNγ cytokines to attract other innate immune cells [113].
The primary function of γδ T cells is to recognize stressed, transformed, and tumor cells, and their killing by perforins and granzymes [114][115]. The mode of action of γδ T cells in chickens is still unclear, but a recent study demonstrated that γδ T cells show killing of LSCC-RP9 cells [109].
γδ T cells are abundantly present in the chicken intestine. It has been shown that the percentage of γδ T cells among IEL population in the ileum of the chicken intestine remained the same during late embryonic days and early post-hatch days but started to increase from day 14 to day 21 post-hatch. As compared to other T cell subsets in the chicken intestine such as CD8αα and CD8αβ T cells, the presence of γδ T cells is lower in chickens younger than 7 days of age, but from day 14 onwards their number becomes similar to CD8αα and CD8αβ T cells [11].


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