Type 1 innate lymphoid cells are associated with type 2 diabetes

AimType 1 innate lymphoid cells (ILC1s) play a major role in regulating systemic inflammatory diseases. However, the relationship between ILC1s and type 2 diabetes (T2D) remains unclear. Thus, the present study investigated the relationship between ILC1s and glucose homoeostasis in humans.MethodsA total of 37 newly diagnosed T2D patients and 32 subjects with normal glucose tolerance (NGT), matched for age and body mass index (BMI), were enrolled in the study. Flow cytometric analysis of ILC1s derived from peripheral blood mononuclear cells (PBMCs) and omental adipose tissue was performed.ResultsT2D patients displayed greater numbers and frequencies of circulating and adipose tissue ILC1s (P < 0.05) compared with NGT subjects, and the two types of ILC1s correlated positively with each other. Circulating ILC1s were positively associated with glycated haemoglobin (HbA_1c), fasting plasma glucose (FPG), homoeostasis model assessment for insulin resistance (HOMA-IR), adipose tissue insulin resistance index (Adipo-IR) and serum free fatty acids (FFAs). A logistic regression model revealed that patients with higher ILC1 levels exhibited a 13.481-fold greater risk of developing T2D.ConclusionThis study is the first to provide evidence that ILC1 abnormalities are involved in the development of diabetes. The data also suggest a potential role of ILC1s as therapeutic indicators in the treatment of T2D.     

HBV感染对肝脏自然杀伤细胞和固有淋巴样细胞22的影响

目的探讨HBV感染对肝脏自然杀伤细胞(NK细胞)和固有淋巴样细胞(ILC)22的影响,为阐明HBV感染诱导机体固有免疫应答的机制提供理论和实验依据。方法选取6~8周龄雄性BALB/c小鼠10只,随机分为实验组和对照组,每组各5只。实验组小鼠经尾静脉高压注射含10μg HBV全基因组质粒的生理盐水(体积相当于9%小鼠体质量);对照组小鼠仅注射生理盐水。4 d后处死小鼠,分离肝脏内淋巴细胞,应用流式细胞术检测肝脏内淋巴细胞中NK细胞亚群和ILC22细胞亚群的比例。组间比较采用t检验。结果高压尾静脉注射HBV全基因组质粒可诱导小鼠产生高水平的HBs Ag和HBe Ag,伴有血清ALT水平升高。实验组小鼠肝脏内NK细胞的比例较对照组小鼠显著升高[(25.90±4.92)%vs(12.98±2.13)%,t=3.811,P=0.003],但CD127+NK细胞和CD127-NK细胞亚群在NK细胞中所占比例在2组之间差异均无统计学意义(P值均0.05)。实验组小鼠肝脏内NKp46+ILC22细胞亚群比例较对照组明显升高[(36.05±6.85)%vs(10.22±3.54)%,t=7.372,P0.001],但NKp46-ILC22细胞亚群的比例在2组之间差异无统计学意义(P0.05)。结论 HBV感染可诱导肝脏内NK细胞和NKp46+ILC22水平升高,从而促进肝脏固有免疫应答。     

HTLV-1 and innate immunity

Innate immunity plays a critical role in the host response to a viral infection. The innate response has two main functions. First, it triggers effector mechanisms that restrict the infection. Second, it primes development of the adaptive response, which completes the elimination of the pathogen or of infected cells. In vivo, HTLV-1 infects T lymphocytes that participate in adaptive immunity but also monocytes and dendritic cells that are major players in innate immunity. Herein, we will review the interplay between HTLV-1 and innate immunity. Particular emphasis is put on HTLV-1-induced alteration of type-I interferon (IFN-I) function. In vitro, the viral Tax protein plays a significant role in the alteration of IFN synthesis and signaling. Despite this, IFN-I/AZT treatment of Adult T-cell Leukemia/Lymphoma (ATLL) patients leads to complete remission. We will discuss a model in which exogenous IFN-I could act both on the microenvironment of the T-cells to protect them from infection, and also on infected cells when combined with other drugs that lead to Tax down-regulation/degradation.     

Spatial distribution of LTi-like cells in intestinal mucosa regulates type 3 innate immunity

Lymphoid tissue inducer (LTi)-like cells are tissue resident innate lymphocytes that rapidly secrete cytokines that promote gut epithelial integrity and protect against extracellular bacterial infections.Here, we report that the retention of LTi-like cells in conventional solitary intestinal lymphoid tissue (SILT) is essential for controlling LTi-like cell function and is maintained by expression of the chemokine receptor CXCR5. Deletion of Cxcr5 functionally unleashed LTi-like cells in a cell intrinsic manner, leading to uncontrolled IL-17 and IL-22 production. The elevated production of IL-22 in Cxcr5-deficient mice improved gut barrier integrity and protected mice during infection with the opportunistic pathogen Clostridium difficile. Interestingly, Cxcr5^−/− mice developed LTi-like cell aggregates that were displaced from their typical niche at the intestinal crypt, and LTi-like cell hyperresponsiveness was associated with the local formation of this unconventional SILT. Thus, LTi-like cell positioning within mucosa controls their activity via niche-specific signals that temper cytokine production during homeostasis.

Lymphoid tissue inducer (LTi)-like cells belong to a family of tissue resident innate lymphocytes that lack rearranged antigen-specific receptors and act as a first line of defense at barrier tissues. LTi-like cells, along with other group 3 innate lymphoid cells (ILC3), maintain intestinal homeostasis by producing the cytokines IL-22 and IL-17A, which promote gut epithelial cell proliferation, anti-microbial peptide production, and tight junction protein abundance (1, 2). The conditioning of epithelial cells by these cytokines contributes to balanced interactions between the host and commensal microbiota under steady-state conditions, and LTi-like cell-derived IL-22 promotes barrier integrity and protective immunity during infection with the enteric pathogenic bacteria (3).In addition to providing effector functions, LTi-like cells and their fetal LTi counterparts are required for early steps in lymphoid tissue development. Fetal LTi induce lymph node and Peyer’s patch development during gestation by activating lymphoid tissue organizer cells at primordial lymphoid organs with lymphotoxin (LT)-α1β2 (4–6). Similarly, LTi-like cells are required for the postnatal development of cryptopatches, small lymphoid aggregates in the intestine that have the potential to mature into isolated lymphoid follicles (ILF) in response to signals from microbes (7, 8). In line with their roles in lymphoid tissue organogenesis and maturation, LTi-like cells in adult mouse intestines preferentially localize in solitary intestinal lymphoid tissue (SILT). The microenvironments of these highly specialized niches are expected to support and regulate LTi-like cells; however, their impact on LTi-like cell behavior has not been fully explored.LTi-like cells express multiple G protein–coupled receptors that facilitate their migration in tissue (9–12). Among these, CXCR5 has a predominant role in the migration of LTi to developing lymphoid structures, with Cxcr5^−/− mice exhibiting defects in lymph node and Peyer’s patch development (13). Mice deficient in CXCR5 or its ligand CXCL13 also have delayed cryptopatch development and fail to convert cryptopatches to mature ILF because of impaired recruitment of B cells to these structures (14–16). Dendritic cells (DCs) have been shown to be a local source of CXCL13 in SILT (16) and thus likely retain B cells and LTi-like cells at these structures under homeostatic conditions via the CXCL13–CXCR5 signaling axis. The retention of LTi-like cells in SILT is expected to bring these cells in close proximity to activating and inhibitory signals provided by specialized myeloid cells, neurons that express the vasoactive intestinal peptide (VIP), and lymphocyte populations localized at these sites (17–20). However, the impact of CXCR5 on functions of LTi-like cells beyond those associated with lymphoid tissue maintenance and development remains unknown.In the current study, we show that CXCR5 expression regulates LTi-like cell function. Deletion of Cxcr5 led to increased numbers of LTi-like cells in the small intestine (SI) and enhanced their ability to produce IL-17A and IL-22. Cxcr5 regulated LTi-like cells via a cell-intrinsic mechanism that did not involve direct suppression by CXCL13. Heightened LTi-like cell activity in Cxcr5-deficient mice was associated with the development of abnormal LTi-like cell aggregates in the SI that were localized in villus lamina propria instead of at the intestinal crypt base. Importantly, augmented production of IL-22 in Cxcr5^−/− mice was protective during acute infection with the opportunistic pathogen Clostridium difficile. These data reveal that CXCR5-dependent migration can control innate type 3 immunity by altering the niche of LTi-like cells in intestinal lamina propria.     

Interactions between the intestinal microbiota and innate lymphoid cells

The mammalian intestine must manage to contain 100 trillion intestinal bacteria without inducing inappropriate immune responses to these microorganisms. The effects of the immune system on intestinal microorganisms are numerous and well-characterized, and recent research has determined that the microbiota influences the intestinal immune system as well. In this review, we first discuss the intestinal immune system and its role in containing and maintaining tolerance to commensal organisms. We next introduce a category of immune cells, the innate lymphoid cells, and describe their classification and function in intestinal immunology. Finally, we discuss the effects of the intestinal microbiota on innate lymphoid cells.     

Critical coordination of innate immune defense against Toxoplasma gondii by dendritic cells responding via their Toll-like receptors

Toll-like receptors (TLRs) play an important role in host defense against a variety of microbial pathogens. We addressed the mechanism by which TLRs contribute to host defense against the lethal parasite Toxoplasma gondii by using mice with targeted inactivation of the TLR adaptor protein myeloid differentiation primary response gene 88 (MyD88) in different innate cell types. Lack of MyD88 in dendritic cells (DCs), but not in macrophages or neutrophils, resulted in high susceptibility to the T. gondii infection. In the mice deficient in MyD88 in DCs, the early IL-12 response by DCs was ablated, the IFN-γ response by natural killer cells was delayed, and the recruited inflammatory monocytes were incapable of killing the T. gondii parasites. The T-cell response, although attenuated in these mice, was sufficient to eradicate the parasite during the chronic stage, provided that defects in DC activation were compensated by IL-12 treatment early after infection. These results demonstrate a central role of DCs in orchestrating the innate immune response to an intracellular pathogen and establish that defects in pathogen recognition by DCs can predetermine sensitivity to infection.     

Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response

Natural killer (NK) cells are abundant in the normal liver, accounting for around one-third of intrahepatic lymphocytes and are important in the defence against hepatitis B virus (HBV) infection as innate immune responses. In this review, we discuss the mechanisms of hepatic NK cell activity against HBV. Whether directly activated by HBV infection or indirectly activated by other lymphocytes such as NKT cells or antigen-presenting cells (APCs), hepatic NK cells exert their anti-viral functions by natural cytotoxicity and production of high levels of cytokines. However, activated NK cells play an important role in regulating adaptive immune responses by interaction with other lymphocytes such as T, B and APCs. In addition, NK cells may contribute to the lymphocyte-mediated liver injury during HBV infection that was previously considered to be mediated only by CD8+ T cells or/and NKT cells.     

Ⅱ型固有淋巴细胞与支气管哮喘的最新研究进展

Ⅱ型固有淋巴细胞(group 2 innate lymphoid cells,ILC2s)是最近才被发现的一类固有淋巴细胞群,并被认为是Th2型细胞因子的主要来源.目前,ILC2s在哮喘中的作用已引起广泛关注.当致敏原刺激气道上皮细胞后,上皮细胞来源的细胞因子IL-33、IL-25、TSLP激活ILC2s,诱导ILC2s产生大量的Th2型细胞因子以及某些生长因子如双调蛋白,这与哮喘的发生以及上皮细胞的修复密切相关.ILC2s不仅能与其他固有免疫细胞相互作用,还可以调控适应性免疫应答,在过敏性炎症反应中起着连接固有免疫与适应性免疫的桥梁作用.本文主要综述ILC2s的调控与功能以及ILC2s在哮喘发病中的最新研究进展.     

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33_95–270, IL-33_107–270, and IL-33_109–270, were 30-fold more potent than full-length human IL-33_1–270 for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33–dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66–111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33–mediated responses in allergic asthma and other inflammatory diseases.Interleukin-33 (IL-33), previously known as nuclear factor from high endothelial venules or NF-HEV (1, 2), is an IL-1 family cytokine (3) that signals through the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2 (4, 5) and induces expression of cytokines and chemokines in various immune cell types, including mast cells, basophils, eosinophils, Th2 lymphocytes, invariant natural killer T, and natural killer cells (3, 4, 6–8). Studies in IL-33–deficient mice indicate that IL-33 plays important roles in type-2 innate immunity and innate-type allergic airway inflammation (9–13). Indeed, IL-33 is a key activator of the recently described group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes) (14–17). These cells control eosinophil homeostasis in blood and adipose tissue (18, 19) and produce extremely high amounts of the type-2 cytokines IL-5 and IL-13 in response to IL-33 (14–16). ILC2s also play important roles in allergic airway inflammation (20–24), atopic skin disease (25–28), helminth infection in the intestine (11, 12, 14–16), and influenza virus infection in the lungs (29, 30).Based on animal model studies and analyses of diseased tissues from patients, IL-33 has been proposed as a candidate therapeutic target for several important diseases, including asthma and other allergic diseases, rheumatoid arthritis, inflammatory bowel diseases, and cardiovascular diseases (4, 6). IL-33 is likely to play a critical role in asthma because the IL33 and IL1RL1/ST2 genes have been reproducibly identified as major susceptibility loci in several independent large-scale genome-wide association studies of human asthma (31, 32).Despite these important advances into the roles of IL-33, very little is known yet about the mechanisms regulating its activity. Full-length human IL-33 is a 270 amino acid protein localized in the nucleus of endothelial and epithelial cells in blood vessels and epithelial barrier tissues (1, 2, 33, 34), which associates with chromatin (2) and histones H2A-H2B, through a short chromatin-binding motif located in its N-terminal part (amino acids 40–58) (35). IL-33 can be released in the extracellular space upon cellular damage or necrotic cell death (36, 37), and it was thus proposed to function as an alarmin (alarm signal or endogenous danger signal), which alerts the immune system to tissue injury following trauma or infection (33, 36, 37).Proteases have been shown to regulate IL-33 activity. Full-length IL-33_1–270 is biologically active but processing by caspases after residue Asp₁₇₈ in the IL-1–like cytokine domain results in its inactivation (36, 37). In contrast, inflammatory proteases from neutrophils, cathepsin G, and elastase, process full-length IL-33 into mature forms that contain an intact IL-1–like cytokine domain and that have an increased biological activity compared with full-length IL-33_1–270 (38). Although neutrophils have been implicated in virus-induced exacerbations of asthma, they are unlikely to be involved in the processing of IL-33 during allergic inflammation. We therefore investigated the possibility that other cell types may be involved in this process. Mast cells, which are widely recognized for their roles as effector cells in allergic disorders, were good candidates because they interact directly with ILC2s in vivo (26) and they are strategically positioned close to vessel walls and epithelial surfaces exposed to the environment (39), the major sites of IL-33 expression (33, 34). We now demonstrate that activated human mast cells and purified mast cell proteases, tryptase and chymase, generate mature forms of IL-33 (IL-33_95–270, IL-33_107–270, and IL-33_109–270), which are ∼30-fold more potent than full-length IL-33_1–270 for activation of ILC2s ex vivo. These IL-33 mature forms are also potent inducers of ILC2s, eosinophils, and type-2 cytokines in vivo. Our study suggests that release of the C-terminal IL-1–like cytokine domain, through proteolytic maturation within the central cleavage/activation domain (amino acids 66–111), is important for full biological activity of IL-33.     

IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis

Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell–mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.Disease conditions associated with pulmonary fibrosis are often progressive and have a poor long-term prognosis (1). In the context of developing new treatments for pulmonary fibrosis, the cytokines associated with the pathogenic milieu that can lead to aberrant extracellular matrix deposition are key targets, in particular interleukin (IL)-13, TGF-β, and, more recently, IL-17A (2). However, to develop more effective therapeutics for fibrotic lung diseases a greater understanding of the pathogenesis and the underlying mechanisms that lead to pulmonary fibrosis is needed (3, 4).The cytokine IL-13 was first implicated in fibrosis using profibrotic eggs from the type 2 cytokine-inducing pathogen Schistosoma mansoni, in the presence of a soluble IL-13Rα2-Fc fusion protein (5) and in Il13^−/− mice (6). IL-13 is now widely linked to a range of fibrotic conditions (7) including asthma, where IL-13 is being targeted as a therapy (8). In the context of the cellular source of IL-13 in the generation of fibrosis, CD4⁺ T helper (h) 2 cells are implicated (9). However, more recently innate lymphoid cells (ILC) are emerging as an important source of IL-13 (10, 11). In this context, the type 2 cytokine IL-25 is implicated in the generation of the recently identified IL-13–expressing ILC, termed ILC2 (11–14).Recent studies have implicated IL-25 and ILC2 in the pathogenesis of pulmonary conditions in both murine models and human conditions such as allergic asthma (12, 13, 15, 16). In murine studies intranasal administration of IL-25 results in evidence of pulmonary tissue remodeling including development of perivascular fibrosis, and intratracheal administration results in increased pulmonary Th2 cytokines and airways hyper-reactivity (AHR) (17, 18), whereas blocking IL-25 reduces AHR severity (19). Herein we describe a potential role for IL-25 in the generation of pulmonary fibrosis in experimental mouse models, via the activation of IL-13–producing ILC2. We also observe increases in both IL-25 and ILC2 in the lung of patients with idiopathic pulmonary fibrosis (IPF). These data suggest unique mechanisms for the generation of pulmonary fibrosis and identify an interesting area for further research on the role of IL-25 and ILC2 in the treatment of pulmonary fibrosis.     

Airway innate lymphoid cells in the induction and regulation of allergy

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models.     

Roles of liver innate immune cells in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding th...     

Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2/ErbB-2), has become the mainstay of treatment for HER2-positive breast cancer. Nevertheless, its exact mechanism of action has not been fully elucidated. Although several studies suggest that Fc receptor-expressing immune cells are involved in trastuzumab therapy, the relative contribution of lymphocyte-mediated cellular cytotoxicity and antitumor cytokines remains unknown. We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL. Our study thus challenges the notion that classical antibody-dependent, lymphocyte-mediated cellular cytotoxicity is important for trastuzumab. We demonstrate that anti-ErbB-2 mAb therapy of experimental tumors derived from MMTV-ErbB-2 transgenic mice triggers MyD88-dependent signaling and primes IFN-γ-producing CD8+ T cells. Adoptive cell transfer of purified T cell subsets confirmed the essential role of IFN-γ-producing CD8+ T cells. Notably, anti-ErbB-2 mAb therapy was independent of IL-1R or IL-17Ra signaling. Finally, we investigated whether immunostimulatory approaches with antibodies against programmed death-1 (PD-1) or 41BB (CD137) could be used to capitalize on the immune-mediated effects of trastuzumab. We demonstrate that anti-PD-1 or anti-CD137 mAb can significantly improve the therapeutic activity of anti-ErbB-2 mAb in immunocompetent mice.     

2型固有淋巴细胞在过敏性疾病发生中的作用

过敏性疾病尤其是支气管哮喘(简称哮喘)一直被认为是由Th2细胞介导的炎症反应.近期研究发现,2型固有淋巴细胞(type-2 innate lymphoid cell,ILC2)作为一种先天性免疫细胞,同样参与哮喘发生的始动环节.该细胞可产生Th2型细胞因子IL-13、IL-5从而应答受损上皮组织释放的IL-33及IL-25,不仅仅作用于固有免疫的初级阶段,还介导获得性免疫相关功能,这使得先天性及获得性两种免疫系统之间存在了某种特殊的联系,也给研究过敏性哮喘发生机制带来了新的思路.     

肝脏自然杀伤细胞在慢性肝病中的作用

肝脏自然杀伤细胞（NK）是一种与外周血NK细胞不同的肝脏免疫细胞。近年来研究表明肝脏NK细胞在各种慢性肝脏疾病中起重要作用。包括对抑制病毒感染和肿瘤细胞生长,对抗肝纤维化均有益处,但同时其又刺激肝损伤和抑制肝再生（肝细胞增殖）。本文就肝脏NK细胞的特征、功能以及在各种常见慢性肝病中作用进展作一综述。     

Regulation of type 2 immunity to helminths by mast cells

Recently, we demonstrated a novel role for gastrointestinal mast cells (MCs) in the early events that lead to the generation of Th2 immunity to helminth infection. ( 1) Mice lacking MCs (Kit (W) /Kit (W-v) and Kit (W-Sh) ) showed a significant inhibition of Th2 cell priming following infection with the parasitic helminth Heligmosomoides polygyrus bakeri (Hp). We showed that MCs degranulate during the early stages of infection when the helminth larvae invade the small intestinal tissue. Furthermore, MC degranulation was required for the enhanced expression and production of the tissue-derived cytokines IL-25, IL-33 and TSLP, which are required for the optimal orchestration and priming of type 2 immunity. In this addendum we aim to address several questions raised by our findings - in particular, the mechanisms through which MCs may recognize helminth exposure in the early stages of infection and by which they may enhance expression of critical tissue cytokines thus, enabling Th2 priming. Furthermore, we will discuss these findings in the context of recently described novel innate immune cells, such as type 2 hematopoietic progenitors and type 2 innate lymphoid cells.