This kind of immunity is induced by and conferred resistance against parasitic helminths, but also play pathologic role, promoting acute and chronic inflammatory response against allergens (Pulendran et al., 2010). Type-2 immunity does not fight helminth itself, but it induced other cells types by secreting Th2 cytokines, leading to eosinophilia, elevated IgE, goblet cell metaplasia with enhanced mucus production and smooth muscle hypersensitivity that act to expulse helmith and response to allergen (Price et al., 2010). Although adaptive Th2 cells are important source of these cytokines, however, recent studies had discovered innate immune cells including novel subsets of lineage negative population of cells have an essential role in initiating type-2 immunity in response to allergen and parasitic helminth before a pathogen-specific adaptive immune response is established. They mimic the role of adaptive Th2 cells in secreting Th2 cytokines even though more promptly and less specifically (Price et al., 2010; Eberl., 2010; Koyusu et al., 2010). Studies had found that epithelial cells are crucial in inducing Th2 immune response against helminth and allergen. They produce IL-25 and IL-33 in response to allergen and helminths. The lineage negative population of cells secretes Th2 cytokines (IL-5 and IL-13) upon induced by the epithelial cytokines (Koyusu et al., 2011; Eberl, 2010; Price et al., 2010). Other than innate cells such as eosinophils, basophils and mast cells that had been implicated as a source of innate cells type that produces this Th2 cytokines, the lineage negative lymphoid cells that act early as part of the innate immune response that had been termed as nuocytes, natural helper cells, innate type 2 helper cells (Ih2) and innate lymphoid cells also found to produces Th2 cytokine.
Natural Helper Cells
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Moro et al recent study had found a novel subset of cells that produce Th2 cytokines. These cells are not a lineage committed cells (eg. T-cells) because they does not produce any lineage marker and do not express antigen. However, flow cytometric analysis shown this novel subset of cells does express c-Kit, Sca-1, IL7R and IL33R.These cells were found associated with adipose tissues in peritoneal cavity and this lymphoid cluster was found in both mouse and human mesentery (Moro et al., 2010). Moro and colleagues name this lymphoid cluster as fat-associated lymphoid clusters (FALC). This FALC Lin-c-Kit+Sca-1+ cells were identified to have similar activation properties as one of the innate immune system lymphocytes, the natural killer (NK) cells in the way that both of them only respond to cytokines stimulation and/or cell-surface components rather than specific antigen. The only different is FALC Lin-c-Kit+Sca-1+ cells do not have NK-cell lineage marker and do not bear any receptor found on progenitor cells. Thus, Moro et al describe this cell as natural helper (NH) cells (Strober., 2010). NH cells was found to be a lymphoid lineage that differentiate dependant on IL-7 and need stem cell factor and IL-7 to support their growth as experimental data that show mice that lack this two components do not show sign of NH cells (Koyasu et al., 2011). NH cells play a critical role in immune response against parasitic helminth. Upon helminth infection, epithelial cells, endothelial cells and adipocytes will produces IL-33 and induce high level of IL-5 and IL-13 production by NH cells. The Th2 cytokines that produce by the NH cells will then induce eosinophilia and goblet cell hyperplasia which plays as an important part of early immune response against helminth infection by limiting the helminth invasion before the helminth-specific T cells are induced (refer to Fig. 1)(Koyasu et al., 2011; Moro et al., 2010; Strober., 2010). Although IL-25 produced by eosinophils and basophils also important in inducing Th2 cytokines from NH cells for helminth expulsion, however, it was observed that NH cells do not response to IL-25 without IL-2 (Strober., 2010). Other then aiding in helminth expulsion, NH cells also constitutively secreting IL-5 and IL-6 which both responsible for the regulation of antibody production. IL-5 support the survival of a special population of self-renewing B lymphocytes (B1 cells), which are found abundant in the peritoneal cavity, by supporting the proliferation of self-renewal of B1 cells. B1 cells are crucial in innate-type immune response because they produce natural antibody specifically for components of commonly encountered microorganisms or self antigen (Strober., 2010; Erickson et al., 2001). Besides, NH cells also support the production of IgA from splenic B cells through IL-5 and IL-6 production, proposing the helper function of NH cells (refer to Fig. 1)(Moro et al., 2010; Koyasu et al., 2011).
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Figure 1. Functions of NH cells. (a) Constitutive production of IL-5 and IL-6 support IgA production by splenic B cells and survival of B1 cells. (b) Helminth infection induced high level of IL-5 and IL-13 production by NH cells, leading to eosinophilia and goblet cell hyperplasia. (Figure obtained from Koyasu et al., 2011)
Other than NH cells, another new innate type-2 immune effector leukocyte had been identified. This lineage negative cell can be characterized by several kinds of cell-surface marker that was also found on T-cells such as ICOS, Thy1.2, CCR9, IL-7Rα, IL-17BR (IL-25R), T1/ST2 (IL-33R), and IL-2Rγc. It was reported to be found in a small amount (around 0.2%) inside the spleen, mesenteric lymph node (MLN), and bone marrow of naïve mouse (Neill et al., 2010; Neill et al., 2011). Microassay analysis of this cell could not show any significant gene expression similar with any other known mature leukocyte population (Neill et al., 2010; Neill et al., 2011; Barlow et al., 2011), suggesting that this is a novel subset of cell is beyond discovery. Neill and colleagues named this novel subset of cell as nuocytes (nu means 13th letter in Greek alphabet), due to its ability in secreting high amount IL13 upon IL-25 and IL-33 induction. Parasitic helminth infection will induce secretion of IL-25 and IL-33 from epithelial cells. Nuocytes will increase significantly in tissues where they had been discovered (with the exception of bone marrow) in response to IL-25 and IL-33 (Neill et al., 2010; Neill et al 2011). The ability of nuocytes to expand rapidly in response to Th2 cytokines and capacity to secrete high levels of IL-13 and IL-5 to enhance antigen specific T-cells response make it another crucial subsets of innate type-2 immune effector leukocyte that act for the expulsion of helminth infection (Neill et al., 2010; Neill et al., 2011). Unlike NH cells, nuocytes is capable of respond to IL-25 alone (Koyasu et al., 2010). Neill et al also demonstrate the important of nuocytes surface receptor (IL-17BR) and secretion of IL-13 is crucial in expulsion of helminth parasite by showing IL-17BR-deficient mice fail to induce by IL-25 and secrete IL-13 and lead to failure in expulsion of worm burden. However, expulsion of helmith parasite is a T-cell dependent process. Hence, even though there was present of nuocytes but lack T-cells, nuocytes was also unable to induce worm expulsion too (Neill et al., 2010). Recent study had also proposed that the present of T-cells mediate prolonged nuocyte expansion, migration and survival. However, the mechanism behind this still yet to be discovered (Neill et al., 2010).
Innate Type-2 helper cells (Ih2)
Innate Type-2 helper cell (Ih2) is another innate cell that capable of producing Th2 cytokines that contribute in initiating adaptive immunity. This cells again, was found to be lineage negative and aren't produced any surface marker that characterize other lymphoid cell types (Price et al., 2010). Ih2 was found populate in many organs and are particularly prevalent in liver, spleen, and mesentry according to Price et al. Ih2 represent major innate IL-13 expressing cells (Price et al., 2010; Koyasu et al., 2010). Same as the previous 2 cells types that had been described, Ih2 also being induced to secret Th2 cytokine that promote Type 2 immunity upon helminth infection. Activation of Ih2 cells is sufficient to mediate the major peripheral effect of IL-25, including eosinophilia and worm clearance even in the absent of adaptive immune response (Price et al., 2010; Fort et al., 2001; Hurst et al., 2002; Fallon et al., 2006; Moro et al., 2010; Neill et al., 2010).
Innate Lymphoid cells (ILC)
Innate lymphoid cell (ILC) is a termed that used to indicate a variety of cells types that share common phenotypic and functional features. This cells lack specific antigen receptor but still capable of producing an array of effector cytokines that in variety match that of T helper cell subsets (Spits et al., 2012). ILC serve important roles in lymphoid organogenesis, tissue homeostasis, and antimicrobial immunity as well as inflammation. There are several functionally distinct subsets of ILC that had been identified which are the Natural Killer (NK) cells, Rorγt+ ILCs, and Type 2 ILCs (ILC2). NK cells rely on IL-15 for development and have the ability to kill target cells as well as producing interferon (IFN)-γ. Rorγt+ ILCs have a role in lymphoid organogenesis, tissue repair, mucosal immunity, and mucosal homeostasis. Other than its protective functions, Rorγt+ ILCs also found contributing to mucosal pathology (Spits et al., 2012; Buonocore et al., 2010; Geremia et al., 2011). While for ILC2, it plays important role against helminth infection. For this part, we will mainly focus on ILC2s. ILC2s had been discovered in both mice and human (Spits et al., 2012). ILC2s are derived from lymphoid precursors (Yang et al., 2011) and are IL-2Rγ chain-dependent for their development and survival (Hurst et al., 2002; Moro et al., 2010; Price et al., 2010). Induction of ILC2s by combination of IL-2 and IL-25 or IL-2 and IL-33 (Mjosberg et al., 2011) strongly activate ILC2, result in production of IL-5 and IL-13. IL-5 stimulates proliferation and survival of eosinophils. Studied in mice suggest that FALC-associated ILC2 promote self renewal of peritoneal B1 cells via IL-5 (Moro et al., 2010), suggest the role of ILC2 in maintaining homeostasis of other hematopoietic cells. As for IL-13, it targets a variety of cell types to induced response against helminth infection. Recent studied had identified the role ILC2 create a favorable environment for generation of Th2 cells, which in return maintain IL-13 and IL-5 production by ILC2, proposing the concerted role between ILC2 and Th2 cells that lead to recruitment and activation of other type 2 effector cell types that help in maintaining efficient anti-helminth immune response (Allen et al., 2011; Neill et al., 2010). In contrast to ILC2 role in protective immunity, Mjosberg et al (Mjosberg et al., 2010) found that ILC2 involved in mucosal pathology, type 2 inflammatory disease.
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Figure 2. Role of ILC2 in type 2 immunity. ILC2 response is initiated by IL-25 and IL-33 which are produced by a variety of cells types upon helminth infection and produce IL-5 and IL-13. IL-5 stimulates proliferation and survival of eosinophils. IL-13 targets a variety of cell types which lead to anti-helminth immune response. ILC2 can cross talk with Th2 to sustains Th2 survival and in return maintains efficient Th2 response, which is important in expulsion of helminth infections. (Figure taken from Spits et al., 2012)
Similarities and Differences
In the last part of essay, we will compare and contrast the above cell types. Th2 immune response was mediated by Th2 cytokines (IL-5 and IL-13) and T-cells of Th2 subsets was thought to be the important and abundant source of this cytokines (Wilhelm et al., 2011; Fort et al., 2001; Hurst et al., 2002; Fallon et al., 2006). However, all the novel subsets of innate cells that had been described above are capable of producing high amount of Th2 cytokines upon helminth infection to induce type 2 immune response that result in expulsion of parasitic helminth.
Despite the fact all this novel subsets of innate cells share the same functions, there are some differences between this four innate cell types. NH cells are incapable of response to IL-25 alone without IL-2 but nuocytes are capable of response to IL-25 by itself. Unlike the other 3 recently described TH2 cytokines producing innate cells, NH cells constitutively producing produce Th2 cytokines, supporting the self renewal of B1 cells and enhanced antibodies production from splenic B cells. NH cell was also the only innate cell types of the four that had been found to have tissue repair function following influenza virus infection. It had been suspected that the slight differences in the surface molecular marker between the innate cells that had been contribute to their slight differences in responding cytokines and additional function refer to table 1 and Table 2). Besides, NH cells and ILC2 was found contribute to inflammatory disorders despite their role in protective immunity, while nuocytes and Ih2 haven't yet been identified contributing to any inflammatory disease. Furthermore, the tissue distribution of this four innate cells were different, with NH cells found in fat associated lymphoid tissues, nuocytes in intestine and MLN, Ih2 in spleen, liver and mesentries followed by ILC2 in adult fetal gut and lung. It is suggested that the differences in tissue distribution of these innate cells contribute to their differences.