Network Pharmacology, Molecular Docking and Experimental Exploring Molecular Mechanisms of Yinqiao Anti-Epidemic Formula in Regulating Mucosal Immune System of Respiratory Tract

[Objectives]To explore the molecular mechanisms of Yinqiao anti-epidemic formula(YQAEF)in regulating mucosal immune system of respiratory tract.[Methods]The active components of YQAEF were obtained from the TCMSP database,and RMIS targets were obtained from the GeneCards database.A"YQAEF components-RMIS targets-pathways"network was constructed by analyzing the above data to screen core targets for molecular docking verification.A mouse model of acute upper respiratory tract infection(AURI)was developed.Based on the experimental models,the key pathway target genes screened by network pharmacology were verified in vivo.[Results]The main active components of YQAEF involved in the regulation of the RMIS included quercetin,acetic acid,and raffinose.Key targets,such as angiotensin-converting enzyme(ACE),galactosidase alpha(GLA),matrix metalloproteinase 2(MMP2),Serpin Family E Member 1(SERPINE1),and myeloperoxidase(MPO)and important viral infection and endocrine resistance signaling pathways were included in the regulation of the RMIS with YQAEF.Molecular docking assays showed that the key targets had good binding activities with the components of YQAEF.Based on the results of network pharmacology,key target proteins in ACE,GLA,MMP2,SERPINE1,and MPO were selected for experimental verification.The results showed that ACE/ACE2 and MPO expressions were increased in the oral and throat mucosa of the AURI mice.Under YQAEF treatment,the expression levels of ACE/ACE2 and MPO were decreased.[Conclusions]This study revealed the mechanism of YQAEF in the regulation of RMIS,which is associated with multiple components,targets,and pathways.Further experiments confirmed that YQAEF interfered with MPO and ACE/ACE2 signaling pathways to regulate the RMIS in the oral and throat mucosa tissue of mice with AURI,and provide a new direction for exploring the potential antiviral mechanism of YQAEF.

The mucosal immune system in the oral cavity——an orchestra of T cell diversity

The mucosal immune system defends against a vast array of pathogens, yet it exhibits limited responses to commensal microorganisms under healthy conditions. The oral-pharyngeal cavity, the gateway for both the gastrointestinal and respiratory tracts, is composed of complex anatomical structures and is constantly challenged by antigens from air and food. The mucosal immune system of the oral-pharyngeal cavity must prevent pathogen entry while maintaining immune homeostasis, which is achieved via a range of mechanisms that are similar or different to those utilized by the gastrointestinal immune system. In this review, we summarize the features of the mucosal immune system,focusing on T cell subsets and their functions. We also discuss our current understanding of the oral-pharyngeal mucosal immune system.

The development and role of microbialhost interactions in gut mucosal immune development

At birth the piglet＇s immune system is immature and it is dependent upon passive maternal protection until weaning.The piglet＇s mucosal immune system develops over the first few weeks but has not reached maturity at weaning ages which are common on commercial farms. At weaning piglets are presented with a vast and diverse range of microbial and dietary/environmental antigens. Their ability to distinguish between antigens and mount a protective response to potential pathogens and to develop tolerance to dietary antigens is critical to their survival and failure to do so is reflected in the high incidence of morbidity and mortality in the post-weaning period. A growing recognition that the widespread use of antibiotics to control infection during this critical period should be controlled has led to detailed studies of those factors which drive the development of the mucosal immune system, the role of gut microbiota in driving this process, the origin of the bacteria that colonise the young piglet＇s intestine and the impact of rearing environment. This review briefly describes how the mucosal immune system is equipped to respond ＂appropriately＂ to antigenic challenge and the programmed sequence by which it develops. The results of studies on the critical interplay between the host immune system and gut microbiota are discussed along with the effects of rearing environment. By comparing these with results from human studies on the development of allergies in children, an approach to promote an earlier maturation of the piglet immune system to resist the challenges of weaning are outlined.

Mucosal immune responses to Ichthyophthirius multifiliis in the ocular mucosa of rainbow trout(Oncorhynchus mykiss,Walbaum),an ancient teleost fish

The eye,as a specialized visual organ,is directly exposed to the external environment,and,therefore,it faces constant chal-lenges from external pathogenic organisms and toxins.In the ocular mucosa(OM)of mammals,mucosal-associated lymphoid tissues(MALTs)constitute the primary line of defense.However,the immune defense role of the OM remains unknown in aquatic vertebrates.To gain insights into the immune processes within the OM of teleost fish,we developed an infection model of rainbow trout(Oncorhynchus mykiss)OM using a parasite,Ichthyophthirius multifiliis(Ich).Immunofluorescence,qPCR,and H&E staining revealed that Ich successfully infiltrates the OM of rainbow trout,leading to pathological struc-tural changes,as evidenced by A&B staining.Importantly,the qPCR results indicate an up-regulation of immune-related genes following Ich infection in the OM.Moreover,transcriptome analyses were conducted to detect immune responses and impairments in eye function within the OM of rainbow trout with Ich infection.The results of the transcriptome analysis that Ich infection can cause an extensive immune response in the OM,ultimately affecting ocular function.To the best of our knowledge,our findings represent for the first time that the teleost OM could act as an invasion site for parasites and trigger a strong mucosal immune response to parasitic infection.

Recent progress in application of nanovaccines for enhancing mucosal immune responses

Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines are receiving increasing attention for mucosal vaccination due to their merits in overcoming mucosal immune barriers and in enhancing immunogenicity of the encapsulated antigens.Herein, we summarized several nanovaccine strategies that have been reported for enhancing mucosal immune responses, including designing nanovaccines that have superior mucoadhesion and mucus penetration capacity, designing nanovaccines with better targeting efficiency to M cells or antigen-presenting cells, and co-delivering adjuvants by using nanovaccines. The reported applications of mucosal nanovaccines were also briefly discussed, including prevention of infectious diseases, and treatment of tumors and autoimmune diseases. Future research progresses in mucosal nanovaccines may promote the clinical translation and application of mucosal vaccines.

Dynamic regulation of innate lymphoid cells in the mucosal immune system

The mucosal immune system is considered a local immune system,a term that implies regional restriction.Mucosal tissues are continually exposed to a wide range of antigens.The regulation of mucosal immune cells is tightly associated with the progression of mucosal diseases.Innate lymphoid cells(ILCs)are abundant in mucosal barriers and serve as first-line defenses against pathogens.The subtype changes and translocation of ILCs are accompanied by the pathologic processes of mucosal diseases.Here,we review the plasticity and circulation of ILCs in the mucosal immune system under physiological and pathological conditions.We also discuss the signaling pathways involved in dynamic ILC changes and the related targets in mucosal diseases.

Induction of apoptosis of lymphocytes in ratmucosalimmune system

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Mucosal immune responses and protective efficacy in yellow catfish after immersion vaccination with bivalent inactivated Aeromonas veronii and Edwardsiella ictaluri vaccine

Mucosal vaccination,which has the potential to induce both mucosal and systemic immune responses,is considered the most suitable method of preventing infectious diseases in farmed fish.Aeromonas veronii and Edwardsiella ictaluri are two pathogenic bacteria found in yellow catfish and often infect the fish through mucosal surfaces.Delivery of a bivalent inactivated vaccine by injection has been shown to induce a strong systemic immune response against both bacterial infections.However,mucosal immune responses and protective efficiency induced by this inactivated vaccine administrated via immersion are yet to be investigated.We developed a bivalent vaccine containing formalin-inactivated A.veronii and E.ictaluri and evaluated the immune response in yellow catfish after immersion vaccination using body fluids biochemistry indices,agglutinating antibody titers,and the expression level of immune-related genes in the skin,gills,spleen,and head kidney.The activities of innate immune-related enzymes and specific agglutination antibody titers in body fluids,as well as the expression of innate and adaptive immune-related genes in both the mucosal and systemic tissues of vaccinated fish,were significantly higher than that in control fish.Next,we assessed the protective efficacy by a challenge model of virulent strains of E.ictaluri and A.veronii.The relative survival percent of vaccinated fish was 80%and 87%after challenging fish with E.ictaluri and A.veronii,respectively,which was higher than unvaccinated control fish(43%and 57%).These results confirm that the bivalent inactivated vaccine administered via immersion induces a strong mucosal immune response and confers good protection against both E.ictaluri and A.veronii.Our results also reinforce the notion that immersion vaccination could stimulate both mucosal and systemic immunity contributing to protection against pathogens.

Gut health:The results of microbial and mucosal immune interactions in pigs

There are a large number of microorganisms in the porcine intestinal tract.These microorganisms and their metabolites contribute to intestinal mucosal immunity,which is of great importance to the health of the host.The host immune system can regulate the distribution and composition of intestinal mi-croorganisms and regulate the homeostasis of intestinal flora by secreting a variety of immune effector factors,such as mucin,secretory immunoglobulin A(sIgA),regenerating islet-derivedⅢ(RegⅢ)γ,and defensin.Conversely,intestinal microorganisms can also promote the differentiation of immune cells including regulatory T cells(Treg)and Th17 cells through their specific components or metabolites.Studies have shown that imbalances in the intestinal flora can lead to bacterial translocation and compromised intestinal barrier function,affecting the health of the body.This review focuses on the composition of the pig intestinal flora and the characteristics of intestinal mucosal immunity,discusses the interaction mechanism between the flora and intestinal mucosal immunity,as well as the regulation through fecal microbiota transplantation(FMT),dietary nutritional composition,probiotics and pre-biotics of pig intestinal microecology.Finally,this review provides insights into the relationship between intestinal microorganisms and the mucosal immune system.

Characteristics of glucose and lipid metabolism and the interaction between gut microbiota and colonic mucosal immunity in pigs during cold exposure

Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold and non-cold adaptation regarding glucose and lipid metabolism,gut microbiota and colonic mucosal immunological features in pigs are unknown.This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation.Moreover,the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs.Results Cold and non-cold-adapted models were established by Min and Yorkshire pigs.Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models(Yorkshire pigs),decreasing plasma glucose concentrations.In this case,cold exposure enhanced the ATGL and CPT-1αexpression to promote liver lipolysis and fatty acid oxidation.Meanwhile,the two probiotics(Collinsella and Bifidobacterium)depletion and the enrichment of two pathogens(Sutterella and Escherichia-Shigella)in colonic microbiota are not conducive to colonic mucosal immunity.However,glucagon-mediated hepatic glycogenolysis in cold-adapted pig models(Min pigs)maintained the stability of glucose homeostasis during cold exposure.It contributed to the gut microbiota(including the enrichment of the Rikenellaceae RC9 gut group,[Eubacterium]coprostanoligenes group and WCHB1-41)that favored cold-adapted metabolism.Conclusions The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa.During non-cold adaptation,cold-induced glucose overconsumption promotes thermogenesis through lipolysis,but interferes with the gut microbiome and colonic mucosal immunity.Furthermore,glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.

Effects of lactic acid bacteria-fermented formula milk supplementation on ileal microbiota,transcriptomic profile,and mucosal immunity in weaned piglets

Background:Lactic acid bacteria(LAB)participating in milk fermentation naturally release and enrich the fermented dairy product with a broad range of bioactive metabolites,which has numerous roles in the intestinal health-promot-ing of the consumer.However,information is lacking regarding the application prospect of LAB fermented milk in the animal industry.This study investigated the effects of lactic acid bacteria-fermented formula milk(LFM)on the growth performance,intestinal immunity,microbiota composition,and transcriptomic responses in weaned piglets.A total of 24 male weaned piglets were randomly divided into the control(CON)and LFM groups.Each group consisted of 6 replicates(cages)with 2 piglets per cage.Each piglet in the LFM group were supplemented with 80 mL LFM three times a day,while the CON group was treated with the same amount of drinking water.Results:LFM significantly increased the average daily gain of piglets over the entire 14 d(P<0.01)and the average daily feed intake from 7 to 14 d(P<0.05).Compared to the CON group,ileal goblet cell count,villus-crypt ratio,sIgA,and lactate concentrations in the LFM group were significantly increased(P<0.05).Transcriptomic analysis of ileal mucosa identified 487 differentially expressed genes(DEGs)between two groups.Especially,DEGs involved in the intestinal immune network for IgA production pathways,such as polymeric immunoglobulin receptor(PIGR),were significantly up-regulated(P<0.01)by LFM supplementation.Moreover,trefoil factor 2(TFF2)in the LFM group,one of the DEGs involved in the secretory function of goblet cells,was also significantly up-regulated(P<0.01).Sequenc-ing of the 16S rRNA gene of microbiota demonstrated that LFM led to selective enrichment of lactate-producing and short-chain fatty acid(SCFA)-producing bacteria in the ileum,such as an increase in the relative abundance of Entero-coccus(P=0.09)and Acetitomaculum(P<0.05).Conclusions:LFM can improve intestinal health and immune tolerance,thus enhancing the growth performance of weaned piglets.The changes in microbiota and metabolites induced by LFM might mediate the regulation of the secretory function of goblet cells.

Olive oil ameliorate allergic response in ovalbumin-induced food allergy mouse by promoting intestinal mucosal immunity

The numerous health benefits of olive oil are widely known,however,it also provides anti-allergic properties that have not yet been fully defined.In this study,the anti-allergic activity of olive oil was evaluated by analyzing the clinical symptoms and immune-related factors in BALB/c mice that had ingested600 mg/(kg·day)olive oil for two weeks prior to the evaluation.An allergy model was subsequently constructed for analysis,the results of which showed that the olive oil reduced the scores of allergic symptoms in the mice,and up-regulated the hypothermia and the decline in the immune organ index.Moreover,fewer allergy-related cytokines and reduced intestinal inflammation was discovered in the olive oil-treated group.In addition,analysis of intestinal mucosal immune-related factors revealed that the olive oil promoted the expression of intestinal tight junction proteins(Claudin-1,Occludin,and ZO-1)and IL-22,and helped maintain the integrity of the intestinal epithelial physical barrier.Increased levels of mucin 2 andβ-defensin were also found in the intestinal mucus of the olive oil-treated mice.These findings suggest that the oral administration of olive oil effectively attenuated the ovalbumin-induced allergic immune response in the mice,and had a positive effect on intestinal epithelial mucosal immunity.

Immune Responses to the Attenuated Mycoplasma hyopneumoniae 168 Strain Vaccine by Intrapulmonic Immunization in Piglets

To investigate the immune responses to the attenuated Mycoplasma hyopneumoniae 168 strain vaccine, 8-15 d old piglets were immunized with M. hyopneurnoniae 168 strain vaccine by intrapulmonic route. And the specific IgG antibody in serum, lymphoproliferation, IFNT, and specific secretory IgA （SIgA） antibody in bronchoalveolar lavage fluid were detected on 30 and 60 d post-immunization （DPI）, respectively. On 60 DPI, all the pigs except for those in health control group were challenged with a field M. hyopneumoniae strain JS. Necropsy was performed on 30 d post-challenge （DPC）. The results showed that IFN7 and specific SIgA were stimulated on surface of respiratory tract after immunization. And peripheral blood mononuclear cells could also be proliferated about 1.81 and 2.12 fold on 30 and 60 DPI when stimulated by M. hyopneumoniae protein in vitro. However, no serum IgG antibody against M. hyopneumoniae was detected during the whole immune phage. After challenge, vaccinated pigs were observed with only very slight histological lesion in individual lobes. None of vaccinated pigs showed any clinical signs. While the unvaccinated pigs from challenge control group showed varying degrees of clinical sign and severe macroscopical lesion of mycoplasmal pneumonia of swine （MPS）. The result suggested that the attenuated M. hyopneumoniae 168 strain vaccine inoculated by intrapulmonic route could activate the systemic cellular immunity, the local mucosal immunity and IFNγ secretion in respiratory tract to against M. hyopneumoniae infection in piglets.

Mucosal COVID-19 vaccines:Risks,benefits and control of the pandemic

Based on mucosal immunization to promote both mucosal and systemic immune responses,next-generation coronavirus disease 2019(COVID-19)vaccines would be administered intranasally or orally.The goal of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines is to provide adequate immune protection and avoid severe disease and death.Mucosal vaccine candidates for COVID-19 including vector vaccines,recombinant subunit vaccines and live attenuated vaccines are under development.Furthermore,subunit protein vaccines and virus-vectored vaccines have made substantial progress in preclinical and clinical settings,resulting in SARS-CoV-2 intranasal vaccines based on the previously successfully used nasal vaccines.Additional to their ability to trigger stable,protective immune responses at the sites of pathogenic infection,the development of‘specific’mucosal vaccines targeting coronavirus antigens could be an excellent option for preventing future pandemics.However,their efficacy and safety should be confirmed.

Intestinal mucosal barrier in functional constipation:Dose it change?

BACKGROUND The intestinal mucosal barrier is the first line of defense against numerous harmful substances,and it contributes to the maintenance of intestinal homeostasis.Recent studies reported that structural and functional changes in the intestinal mucosal barrier were involved in the pathogenesis of several intestinal diseases.However,no study thoroughly evaluated this barrier in patients with functional constipation(FC).AIM To investigate the intestinal mucosal barrier in FC,including the mucus barrier,intercellular junctions,mucosal immunity and gut permeability.METHODS Forty FC patients who fulfilled the Rome IV criteria and 24 healthy controls were recruited in the Department of Gastroenterology of China-Japan Friendship Hospital.The colonic mucus barrier,intercellular junctions in the colonic epithelium,mucosal immune state and gut permeability in FC patients were comprehensively examined.Goblet cells were stained with Alcian Blue/Periodic acid Schiff(AB/PAS)and counted.The ultrastructure of intercellular junctional complexes was observed under an electron microscope.Occludin and zonula occludens-1(ZO-1)in the colonic mucosa were located and quantified using immunohistochemistry and quantitative real-time polymerase chain reaction.Colonic CD3+intraepithelial lymphocytes(IELs)and CD3+lymphocytes in the lamina propria were identified and counted using immunofluorescence.The serum levels of D-lactic acid and zonulin were detected using enzyme-linked immunosorbent assay.RESULTS Compared to healthy controls,the staining of mucus secreted by goblet cells was darker in FC patients,and the number of goblet cells per upper crypt in the colonic mucosa was significantly increased in FC patients(control,18.67±2.99;FC,22.42±4.09;P=0.001).The intercellular junctional complexes in the colonic epithelium were integral in FC patients.The distribution of mucosal occludin and ZO-1 was not altered in FC patients.No significant differences were found in occludin(control,5.76E-2±1.62E-2;FC,5.17E-2±1.80E-2;P=0.240)and ZO-1(control,2.29E-2±0.93E-2;FC,2.68E-2±1.60E-2;P=0.333)protein expression between the two groups.The mRNA levels in occludin and ZO-1 were not modified in FC patients compared to healthy controls(P=0.145,P=0.451,respectively).No significant differences were observed in the number of CD3+IELs per 100 epithelial cells(control,5.62±2.06;FC,4.50±2.16;P=0.070)and CD3+lamina propria lymphocytes(control,19.69±6.04/mm^(2);FC,22.70±11.38/mm^(2);P=0.273).There were no significant differences in serum D-lactic acid[control,5.21(4.46,5.49)mmol/L;FC,4.63(4.31,5.42)mmol/L;P=0.112]or zonulin[control,1.36(0.53,2.15)ng/mL;FC,0.94(0.47,1.56)ng/mL;P=0.185]levels between FC patients and healthy controls.CONCLUSION The intestinal mucosal barrier in FC patients exhibits a compensatory increase in goblet cells and integral intercellular junctions without activation of mucosal immunity or increased gut permeability.

The role of probiotics in prevention and treatment of food allergy

With the prevalence of food allergy increasing every year,food allergy has become a common public health problem.More and more studies have shown that probiotics can intervene in food allergy based on the intestinal mucosal immune system.Probiotics and their metabolites can interact with immune cells and gut microbiota to alleviate food allergy.This review outlines the relationship between the intestinal mucosal immune system and food allergy.This review also presents the clinical application and potential immunomodulation mechanisms of probiotics on food allergy.We aim at providing a reference for further studies to explore the key active substances and immunomodulation mechanisms of anti-allergic probiotics.

Vaccine therapy for dysbiosis-related diseases

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases,such as obesity,diabetes,rheumatoid arthritis,and inflammatory bowel diseases represented by Crohn’s disease and ulcerative colitis.Dysregulated gut microbiome contributes to the pathogenesis of such disorders;however,there are few effective treatments for controlling only disease-mediating bacteria.Here,we review current knowledge about the intestinal microbiome in health and disease,and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides,which we have recently developed.Unlike other conventional injectable immunizations,our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity.This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection,and control metabolic symptoms mediated by intestinal bacteria(e.g.Clostridium ramosum)by induction of high titers of antigen-specific IgA at target mucosal sites.In the future,our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.

The Preventative Effect of Dietary Apostichopus japonicus on Intestinal Microflora Dysregulation in Immunosuppressive Mice Induced by Cyclophosphamide

Sea cucumbers are recognized as food and drug resources with many nutritional benefits, and Apostichopus japonicus is a kind of sea cucumber with good quality. Processing methods have some effect on its quality. This study aimed to explore the effects of Apostichopus japonicus with three different processing methods (dried, instant, and enzymatic sea cucummbers) on intestinal microflora dysregulation using a cyclophosphamide (cy) induced immunosuppressive mouse model. The expression of lysozyme, immunoglobulin A (IgA), and polymeric immunoglobulin receptor (pIgR) in the intestine and gut microbiota were investigated. The results showed that three types of A. japonicus could improve mucosal immunity and regulate gut microbiota. Dietary A. japonicus could reverse microbial imbalance, including increasing the bacterial diversity, enhancing the number of Bifidobacterium, and changing the bacterial composition. The most effect was observed with dried A. japonicus. Expression of lysozyme and IgA in the intestine was significantly increased. This study identified positive effects of dietary A. japonicus on mucosal immunity, particularly on gut microbiota, suggesting that dietary A. japonicus may aid in improving mucosal immunity and preventing exogenous infection. Additionally, the processing method has some effect on immunomodulatory function.

Identification of two pIgR-like molecules in teleost fish with opposite roles in mucosal immunity against bacterial infection

Polymeric immunoglobulin(Ig)receptor-like(pIgRL)molecules have been identified in teleost fish.However,compared to functional studies of their related genes(e.g.,mammalian CD300 family)in eliminating pathogen invasion while preserving homeostasis,the roles of pIgRL in teleost fish remain unclear.In this study,we demonstrated that a pair of pIgRL molecules in zebrafish,pIgRL3.5 and pIgRL4.2,were highly expressed in the intestine and immune cells.Moreover,we constructed an Edwardsiella piscicida infection model,which induced strong inflammatory responses in the zebrafish intestine.Interestingly,pIgRL3.5 and pIgRL4.2 exhibited opposite inducible expression patterns in response to bacterial infection,suggesting that they perform different roles.More importantly,by conducting overexpression and knockdown experiments,our findings demonstrated that zebrafish pIgRL3.5 played a protective role in host defense against E.piscicida infection by inhibiting excessive inflammatory responses.In contrast,pIgRL4.2 facilitated pathogen growth and dissemination in zebrafish intestine.Collectively,our findings are the first to demonstrate that a pair of pIgRL molecules in teleost fish play opposite roles in mucosal immune response to bacterial infection.Therefore,our results provide crucial insights into the conserved role of pIgRL molecules in immune regulatory functions throughout vertebrate evolution.

Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection

The male and female reproductive tracts are complex microenvironments that have diverse functional demands. The immune system in the reproductive tract has the demanding task of providing a protective environment for a fetal allograft while simultaneously conferring protection against potential pathogens. As such, it has evolved a unique set of adaptations, primarily under the influence of sex hormones, which make it distinct from other mucosal sites. Here, we discuss the various components of the immune system that are present in both the male and female reproductive tracts, including innate soluble factors and cells and humoral and cell-mediated adaptive immunity under homeostatic conditions. We review the evidence showing unique phenotypic and functional characteristics of immune cells and responses in the male and female reproductive tracts that exhibit compartmentalization from systemic immunity and discuss how these features are influenced by sex hormones. We also examine the interactions among the reproductive tract, sex hormones and immune responses following HIV-1 infection. An improved understanding of the unique characteristics of the male and female reproductive tracts will provide insights into improving clinical treatments of the immunological causes of infertility and the design of prophylactic interventions for the prevention of sexually transmitted infections.