|Year : 2019 | Volume
| Issue : 3 | Page : 89-95
Gut Immunity – Homeostasis and Dysregulation in Sepsis
Yini Sun1, Mandy L Ford2, Craig M Coopersmith3
1 Department of Surgery, Emory Critical Care Center, Atlanta, GA, USA; Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
2 Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
3 Department of Surgery, Emory Critical Care Center, Atlanta, GA, USA
|Date of Submission||28-Jun-2019|
|Date of Acceptance||28-Aug-2019|
|Date of Web Publication||28-Oct-2020|
Dr. Craig M Coopersmith
Department of Surgery, Emory Critical Care Center, 101 Woodruff Circle, Suite WMB 5105, Atlanta, GA 30322
Source of Support: None, Conflict of Interest: None
The mucosal immune system plays a central role in the pathophysiology of health and disease. As the home to the largest population of lymphocytes in the body, the mucosal immune system closely communicates within other elements of the intestine, with constant cross talk with the gut microbiome and epithelial layer. Further, the gut's immune system plays a central role in communicating with remote organs. The mucosal immune system is critical in preventing autoimmunity, while simultaneously retaining the capacity to respond vigorously to mucosal invaders. This results in a state where the mucosal immune system not only can help restore homeostasis in critical illness but can also worsen inflammation and organ injury in sepsis. The purpose of this minireview is to provide an overview of mucosal immunity in health and in sepsis, with a focus on intraepithelial lymphocytes. Understanding the role of the mucosal immune system in both controlling and propagating sepsis is vital for future efforts designed to target it for therapeutic gain in the intensive care unit.
Keywords: Gut, immune, intestine, mucosa, sepsis
|How to cite this article:|
Sun Y, Ford ML, Coopersmith CM. Gut Immunity – Homeostasis and Dysregulation in Sepsis. J Transl Crit Care Med 2019;1:89-95
| Introduction|| |
The single cell layer intestinal epithelium serves as a barrier between 40 trillion microbes that make up the microbiome and the human host. While the microbiome plays a beneficial role in development and homeostasis, microbes and their products can be deadly if not appropriately compartmentalized. As such, the gut mucosal immune system plays a crucial role in the surveillance of foreign antigens and orchestrating a response when appropriate., This is crucial considering that the mucosal immune system is continuously bombarded with foreign microbial antigens, and the host must perpetually be on watch against invasive pathogens while also allowing the microbiome to not only coexist with the host but also to have bilateral communication with host cells.
To play this crucial role, the mucosal immune system is made up of a number of different cell types that each plays a role in orchestrating the overall host response to acute and chronic antigen stimulation in the gut. The intestine is the largest lymphoid organ of the body, and a variety of immune cells reside between or underneath the epithelial layer. Together, the innate and adoptive immune system communicate and synergize with each other to maintain gut microenvironment homeostasis.
| Gut Immune Cells in Health and Chronic Disease|| |
Intraepithelial lymphocytes (IELs) reside within the gut epithelium where they have immediate access to antigen in the gut lumen and thus function as a specialized antigen-experienced T-cell. There are two types of IELs, with the distinction based on the mechanisms by which they become activated and on the cognate antigens they recognize. Type a IELs (also called induced IELs) are either CD8αβ+ or CD4+ T-cells that express T-cell receptor (TCR)αβ. They arise from conventional T-cells that are activated postthymically in response to peripheral antigen. These represent tissue-resident memory T-cells that are recruited to the epithelium after systemic priming., In contrast, Type b IELs (also called natural IELs), are either CD8αα+ or CD8αα− T-cells that express either TCRαβ or TCRγδ. They acquire their activated phenotype during development in the thymus in the presence of self-antigens and enter the small intestinal epithelium directly upon maturation.
Induced IELs are rare in early life but gradually increase in number with age in response to exogenous antigen.,,,, The development of IELs not only provides protective immunity at the gut mucosa surface but also reduces autoimmune responses directly against innocuous antigens. Natural IELs do not need exogenous antigen so are formed very early in development and thus can be detected in a fetus before birth (before a host is exposed to outside antigen). Over time, a host is exposed to more antigens. As this happens, the population of IELs changes and the host gradually has more Type a IELs than Type b IELs.
A total of 60% of IELs in the small intestine are TCR γδ+. In addition, IELs express the activation markers CD44 and CD69. A hallmark of small intestinal IELs is the expression of CD103 (also known as αE integrin) which interacts with E-cadherin and allows them to home to the small intestine., As might be expected by their location at gut mucosal interface, the presence of microbes in the gut lumen impacts IEL activation and proliferation. Microbial sensing through NOD2 and MyD88 can lead to epithelial production of interleukin (IL)-15, which, in turn, stimulates IEL proliferation and effector function., When IELs are activated, they can express large amounts of biologically active soluble cytokines, such as interferon (IFN)γ, IL-2, IL-4, and IL-17 within hours of activation.,,,,,,,
TCRγδ+ IELs have two (at least) distinct roles in protecting the host. First, these cells control intestinal epithelial cell growth and repair the epithelial barrier.,, As an example, murine colonic IELs promote epithelium barrier function through producing IL-6 in MyD88-dependent manner in response to Citrobacterrodentium infection. In addition, mice lacking TCRγδ+ T-cells have reduced tight junction protein, loss of normal intestinal epithelial cell morphology, reduction of major histocompatibility complex Class II expression by enterocytes, and impairment of mucosal IgA production., TCR γδ+ T-cells also produce keratinocyte growth factor, transforming growth factor-β, and IFNγ, which promotes intestinal epithelial cell proliferation and repair after injury. A complementary role of IELs is immune surveillance in order to avoid mucosal entry of intraluminal microbes and microbial contents. For example, small intestinal γδ+ IELs secrete innate antimicrobial factors in response to resident bacterial pathobionts that penetrate the intestinal epithelium.
Although IELs play important protective and regulatory roles, they also have the potential to cause and/or propagate disease. For instance, Type b γδ+ IELs have been shown to promote immunopathology and inflammation in mice with inflammatory bowel disease.,, In addition, mucosal CD4+-induced IELs can communicate with CD4+ T-cells in the lamina propria to promote the development of small intestine inflammation in patients with celiac diseases.
M cells are located in Peyer's patches, where they comprise 5%–10% of the follicle-associated epithelium. There are short, irregular microvilli on the apical surface of M-cells, which enables them to contact luminal antigen. The intraepithelial pocket beneath the basolateral side of M-cells facilitates pathogen translocation to lymphocytes or antigen-presenting cells, leading to presentation of peptide epitopes to CD4+ T-cells to establish acquired immunity in the gut such that M-cells are “the first entrance” of luminal antigen. M-cells not only play a major role in cross talk with other immune cell population of gut but also provide a platform for developing mucosal vaccines.
Innate lymphoid cells
Innate lymphoid cells (ILCs) are a diverse class of immune cells defined by (a) lymphoid morphology, (b) absence of recombination-associated, gene-mediated antigen receptors, and (c) absence of myeloid and dendritic cell markers. ILCs play a central role in innate immune response to infection, inflammation, and tissue damage, especially in regulating epithelial responses and maintaining intestinal homeostasis. ILCs are divided into three groups based on the cytokine production profile. Group 1 ILCs include natural killer (NK) cells and ILC1 cells and produce IFNγ but no other cytokines associated with Th17 cells. Group 2 ILCs cells are located in the lungs and airways as well as the intestine and mesentery of both humans and mouse and produce TH2- associated cytokines. Group 3 ILCs include all subtypes that produce Th17 cytokines IL-17 and IL-22, which have been implicated in immunity to extracellular bacteria and intestinal inflammation., Signals derived from gut commensal bacteria are recognized by ILC receptors, which can directly regulate ILCs. In addition, selected commensal bacteria reside in dendritic cells and modulate the function of dendritic cells to activate ILC3 cells which subsequently induce the intestinal epithelium to secrete antimicrobial peptides to maintain the balance of intestinal immunity.
The gut is home to the largest population of mast cells in the body. Mast cells regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuroimmune interactions. Microbial translocation leads to mucosal mast cell activation, inflammatory responses, and altered mast cell–enteric nerve interaction. Although an association has been demonstrated between intestinal hyperpermeability and mucosal mast cell activation, the mechanisms linking mast cell activity with altered intestinal barrier in human disease have yet to be elucidated.
Natural killer cells
Intestinal NK cells are scattered in the epithelium and stroma where they contact either microbes or microbial components. In this setting, NK cells interact with epithelial cells, fibroblasts, and multiple different immune cells (macrophages, dendritic cells, and T-lymphocytes). NK cells produce IFNγ, which can lead to recruitment of peripheral NK cells and amplify the host response. While gut NK cells play a role in mucosal immunity, they have also been linked to the pathogenesis of Crohn's disease and ulcerative colitis.
| Gut Immune Dysfunction in Sepsis|| |
Intraepithelial lymphocytes in sepsis
The commonly used intraabdominal sepsis model cecal ligation and puncture (CLP) induces a significant increase of the percentage of CD8+ TCRγδ+ cells with a simultaneous decrease in CD8+ TCRαβ+ percentage. In addition, CLP induces a decline in the ability of IELs to release IL-2 and IFNγ at 24h. This is associated with increased secretion of IL-10 and NO. While no difference was seen in cytokine release in IL-10 knockout mice, this cytokine decline was not seen in iNOS knockout mice, suggesting it is mediated by the NO induction. Early mortality is increased in mice in lacking γδ T-cells following CLP, accompanied by a decrease in plasma IL-6, IL-12, and TNF through suppressing Th1 cytokine release. In addition, CLP induces a lower percentage of CD8αα+ TCRαβ+ IELs and higher messenger RNA expression of complement 5a receptor, IL-2 receptor β, IL-15 receptor α, and IFN-γ by CD8αα+ TCRαβ+ IELs. When septic mice were treated with glutamine, these immunomodulatory-mediator genes decreased and IL-7 receptor and TGB-β expressions increased in CD8αα+ TCRαβ+ IELs associated with decreased apoptosis in CD8αα+ TCRαβ+ IELs. CD8αα+ TCRαβ+ natural IELs express self-reactive TCRs, and under physiological conditions, self-specific CD8αα+ TCRαβ+ IELs protect the intestinal mucosa against chronic inflammation. However, autoreactive IELs might be overactivated in sepsis leading to a higher threshold for TCR activation. Consistent with the contribution of TCRγδ+ IELs in the early host response to infection, these cells limit early bacterial dissemination following infection with Salmonella More Detailsenterica Serovar Typhimurium, as there is a 100-fold increase in bacteria in TCRδ−/− mice compared with wild-type mice 3 h following oral inoculation (although there was no difference at 24–48 h). Similarly, γδ IELs play an essential role in limiting mucosal penetration by intestinal bacteria, associated with production of the antibacterial defensing, RegIIIγ. IELs also have two distinct roles in the response to the murine protozoan pathogen Eimeriavermiformis by production of cytokines to induce protective immunity and expression of junctional molecules to preserve the epithelial barrier. Of note, IELs are kept in a heightened state of activation correlating with alterations in the IEL mitochondrial membrane, especially the cardiolipin composition, and upon inflammation, the cardiolipin composition is altered to support IEL proliferation and effector function. However, when C57Bl/6 mice receive a sublethal dose of LPS, there are no phenotypic changes of IELs. However, IELs display increased cytolytic activity, proliferation, and IFNγ production following LPS administration. Of note, this increased IFNγ production may induce increased NOS-2mRNA seen after endotoxemia.
Innate lymphoid cell 2s in sepsis
Mouse subjected to CLP demonstrated an increase in number and percentage of ILC2s in the small intestine (as well as an increase in the peritoneal cells and a decrease in the liver) 24 h after sepsis. Sepsis also resulted in changes in ILC2 effector cytokine (IL-13) and activating cytokine (IL-33) in the blood of both septic mice and patients in septic shock. These murine changes are abrogated in mice deficient in functionally invariant NKT cells. Further, mice deficient in IL-13-producing cells (including ILC2) have improved survival following sepsis, associated with decreased morphologic evidence of tissue injury and reduced peritoneal IL-10 levels.
Gut immune cross talk
The gut is often referred to as the “motor” of multiple organ dysfunction syndrome. Both the microbiome and the epithelium are extensively injured in sepsis. The microbiome is converted into a pathobiome with a significant loss of diversity and development of numerous virulence factors. The gut epithelium becomes leaky via alterations in tight junctions, leading to hyperpermeability. This is exacerbated by a marked increase in gut epithelial apoptosis, couple with diminished proliferation and slowed migration., None of these processes occurs in isolation, however. A complex “conversation” constantly occurs within the gut as the epithelium, immune system, and microbiome have extensive cross talk, wherein each element profoundly impacts the others, and in turn, is reciprocally impacted.,,,, Of note, IELs have an important role as a first line of defense via cytolysis of dysregulated intestinal epithelial cells and cytokine-mediated regrowth of healthy epithelial cells. In addition, activated IELs provoke Type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium to protect cells against viral infection, such that IEL activation offers a direct means to promote the innate antiviral potential of the intestinal epithelium. In addition, the “gut–lymph hypothesis” postulates that toxic mediators produced in the gut exit via the mesenteric lymph duct, where they cause distant injury in the lung. Ligation of mesenteric lymph duct abrogates lung injury and neutrophil activation, which improves survival in a lethal shock model. In addition, injecting toxic lymph into a healthy animal induces acute lung injury via a TLR4-dependent pathway. Interestingly, gut lymph does not contain intact bacteria or endotoxin, but rather contains protein or lipid factors that stimulate toll-like receptor-4 leading to lung injury.
| Treatments That May Impact Gut Mucosal Immunity in Sepsis|| |
Nutrition support in sepsis
Nutrition support is crucial in sepsis (and critical illnesses in general) in the intensive care unit (ICU). Patients who are not fed have profound immunologic changes, above and beyond the nutritional deficits seen with the obligate catabolic state induced by sepsis. Enteral nutrition augments the host immune response, in addition to its role in providing calories. In addition, route of nutritional administration also significantly impacts the mucosal immune system. Total parenteral nutrition (TPN) in unmanipulated animals induces significant alterations in the phenotypic subpopulations of IELs as well as alterations in IEL gene expression compared to mice that receive enteral nutrition, leading to the potential for significant immunomodulation during the use of TPN. Specifically, 88 IEL genes were upregulated and 114 genes were downregulated in mice receiving TPN. The genes with the highest degree of upregulation were FK506-binding protein 5, mannose-binding lectin, and metallothionein 1, while the genes that had the highest degree of downregulation were microsomal epoxide hydrolase 1 and cytochrome P450 1a1. Nutrition also directly impacts the microbiome, which, in turn, can secondarily alter the immune system. While the majority supporting this link occurs in health, emerging data suggest that nutritional support impacts the microbiome in critical illness as well.
Immunotherapy for sepsis
The success of coinhibition blockade in cancer has led to significant interest in checkpoint inhibitor therapy in sepsis. Robust preclinical data demonstrate that coinhibition blockade – aimed at programmed cell death 1 (PD-1) and its ligand PDL1, cytotoxic T-lymphocyte antigen-4, 2B4, or B- and T-lymphocyte attenuator – improves survival in a wide variety of septic insults.,,,, This has led to the Phase I trials of checkpoint inhibitors in septic patients. The complex and disparate mechanisms through which checkpoint inhibitor blockade improves survival in sepsis is outside the scope of this review. However, it is worth noting that programmed death-ligand 1 (PD-L1) deficiency in mice alters both gut morphology and intestinal permeability following sepsis. Further, PD-L1 knockout mice have reduced tissue levels of IL-6, TNF and MCP-1, as well as prevention of loss of sepsis-induced tight junction protein loss compared to WT mice after sepsis. Further,in vitro evidence demonstrates that PD-L1 expression increases in Caco2 cell monolayers in response to inflammatory cytokine stimulation associated with increased monolayer permeability, while these changes are reversed by blocking PD-L1.
As an immune-boosting agent, IL-7 can lead to the production of naïve T-cells, memory T-cells, central memory T-cells, and CD4+ CD8+ T-cells. Preclinical data demonstrate that IL-7 improves T-cell viability, trafficking, and IFNγ production and leads to a two-fold improvement in survival in mice with polymicrobial sepsis. IL-7 also improves host immunity and survival in a two-hit model of Pseudomonasaeruginosa pneumonia. In addition, a Phase I clinical trial of IL-7 in septic patients demonstrated encouraging results, with a reversal of loss of CD4+ and CD8+ cells. Although the mechanism of IL-7 is complex, IL-7 has been demonstrated to modulate the composition of gut ILCs, suggesting that altering mucosal immunity might play a role in the efficacy of IL-7.
The amino acid glutamine modulates the mucosal immune system in sepsis. A single intravenous dose of glutamine following CLP increases the percentage of CD8αα+ TCRαβ+ IELs, prevents CD8αα+ TCRαβ+ IELs apoptosis, and downregulates CD8αα+ TCRαβ+ IEL-expressed inflammatory mediators, including C5aR, IL-2Rβ, IL-15Rα, and IFNγ. In addition, glutamine prevents TPN-associated IEL-derived cytokine changes, upregulates tight junction protein expression, and preserves the epithelial barrier function. Unfortunately, despite significant preclinical trials supporting its use as well as smaller clinical trials, the largest clinical trial of glutamine in critical illness demonstrated increased mortality in patients randomized to receive glutamine, while supplementing parenteral nutrition with glutamine did not change outcomes in surgical ICU patients. As such, despite its beneficial effects on gut mucosal immunity (and overall gut homeostasis) in murine studies, additional studies are needed to determine if there is a role for glutamine in septic patients.
| Conclusion|| |
The mucosal immune system has a unique role in maintaining health and mediating disease due to its close connections with the gut epithelium, the gut microbiome, as well as the systemic immune system. In its location at the interface of multiple critical biological processes, the mucosal immune system can either help restore homeostasis or propagate disease via alterations in inflammation. Further studies are needed to better understand the role of the mucosal immune system in the pathophysiology and sepsis and whether it can be targeted for therapeutic gain.
Financial support and sponsorship
This work was supported by funding from the National Institutes of Health (GM072808, GM104323, AA027396, GM113228).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Haussner F, Chakraborty S, Halbgebauer R, Huber-Lang M. Challenge to the intestinal mucosa during sepsis. Front Immunol 2019;10:891.
Yap YA, Mariño E. An insight into the intestinal web of mucosal immunity, microbiota, and diet in inflammation. Front Immunol 2018;9:2617.
Klingensmith NJ, Coopersmith CM. The gut as the motor of multiple organ dysfunction in critical illness. Crit Care Clin 2016;32:203-12.
Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 2010;10:159-69.
Kurashima Y, Kiyono H. Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu Rev Immunol 2017;35:119-47.
Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol 2011;11:445-56.
Swamy M, Abeler-Dörner L, Chettle J, Mahlakõiv T, Goubau D, Chakravarty P, et al.
Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance. Nat Commun 2015;6:7090.
Guy-Grand D, Cerf-Bensussan N, Malissen B, Malassis-Seris M, Briottet C, Vassalli P. Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: A role for the gut epithelium in T cell differentiation. J Exp Med 1991;173:471-81.
Hayday A, Theodoridis E, Ramsburg E, Shires J. Intraepithelial lymphocytes: Exploring the third way in immunology. Nat Immunol 2001;2:997-1003.
Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al.
Innate lymphoid cells – A proposal for uniform nomenclature. Nat Rev Immunol 2013;13:145-9.
Hayday A, Gibbons D. Brokering the peace: The origin of intestinal T cells. Mucosal Immunol 2008;1:172-4.
Helgeland L, Brandtzaeg P, Rolstad B, Vaage JT. Sequential development of intraepithelial gamma delta and alpha beta T lymphocytes expressing CD8 alpha beta in neonatal rat intestine: Requirement for the thymus. Immunology 1997;92:447-56.
Manzano M, Abadía-Molina AC, García-Olivares E, Gil A, Rueda R. Absolute counts and distribution of lymphocyte subsets in small intestine of BALB/c mice change during weaning. J Nutr 2002;132:2757-62.
Umesaki Y, Setoyama H, Matsumoto S, Okada Y. Expansion of alpha beta T-cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology 1993;79:32-7.
Steege JC, Buurman WA, Forget PP. The neonatal development of intraepithelial and lamina propria lymphocytes in the murine small intestine. Dev Immunol 1997;5:121-8.
Latthe M, Terry L, MacDonald TT. High frequency of CD8 alpha alpha homodimer-bearing T cells in human fetal intestine. Eur J Immunol 1994;24:1703-5.
Bonneville M, Janeway CA Jr., Ito K, Haser W, Ishida I, Nakanishi N, et al.
Intestinal intraepithelial lymphocytes are a distinct set of gamma delta T cells. Nature 1988;336:479-81.
Cheroutre H. Starting at the beginning: New perspectives on the biology of mucosal T cells. Annu Rev Immunol 2004;22:217-46.
Kilshaw PJ, Murant SJ. A new surface antigen on intraepithelial lymphocytes in the intestine. Eur J Immunol 1990;20:2201-7.
Cepek KL, Shaw SK, Parker CM, Russell GJ, Morrow JS, Rimm DL, et al.
Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 1994;372:190-3.
Kuhn KA, Schulz HM, Regner EH, Severs EL, Hendrickson JD, Mehta G, et al.
Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal Immunol 2018;11:357-68.
Yu Q, Tang C, Xun S, Yajima T, Takeda K, Yoshikai Y. MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8 alpha alpha TCR alpha beta and TCR gamma delta intestinal intraepithelial lymphocytes. J Immunol 2006;176:6180-5.
Jiang W, Wang X, Zeng B, Liu L, Tardivel A, Wei H, et al.
Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J Exp Med 2013;210:2465-76.
Offit PA, Dudzik KI. Rotavirus-specific cytotoxic T lymphocytes appear at the intestinal mucosal surface after rotavirus infection. J Virol 1989;63:3507-12.
Guy-Grand D, Malassis-Seris M, Briottet C, Vassalli P. Cytotoxic differentiation of mouse gut thymodependent and independent intraepithelial T lymphocytes is induced locally. Correlation between functional assays, presence of perforin and granzyme transcripts, and cytoplasmic granules. J Exp Med 1991;173:1549-52.
Ebert EC, Roberts AI. Lymphokine-activated killing by human intestinal lymphocytes. Cell Immunol 1993;146:107-16.
Roberts AI, O'Connell SM, Biancone L, Brolin RE, Ebert EC. Spontaneous cytotoxicity of intestinal intraepithelial lymphocytes: Clues to the mechanism. Clin Exp Immunol 1993;94:527-32.
Chardès T, Buzoni-Gatel D, Lepage A, Bernard F, Bout D. Toxoplasma gondii
oral infection induces specific cytotoxic CD8 alpha/beta+ Thy-1+ gut intraepithelial lymphocytes, lytic for parasite-infected enterocytes. J Immunol 1994;153:4596-603.
Müller S, Bühler-Jungo M, Mueller C. Intestinal intraepithelial lymphocytes exert potent protective cytotoxic activity during an acute virus infection. J Immunol 2000;164:1986-94.
Shires J, Theodoridis E, Hayday AC. Biological insights into TCRgammadelta+and TCRalphabeta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 2001;15:419-34.
Tang F, Chen Z, Ciszewski C, Setty M, Solus J, Tretiakova M, et al.
Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J Exp Med 2009;206:707-19.
Komano H, Fujiura Y, Kawaguchi M, Matsumoto S, Hashimoto Y, Obana S, et al.
Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A 1995;92:6147-51.
Roberts SJ, Smith AL, West AB, Wen L, Findly RC, Owen MJ, et al.
T-cell alpha beta + and gamma delta + deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc Natl Acad Sci U S A 1996;93:11774-9.
Guy-Grand D, DiSanto JP, Henchoz P, Malassis-Séris M, Vassalli P. Small bowel enteropathy: Role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-gamma, TNF) in the induction of epithelial cell death and renewal. Eur J Immunol 1998;28:730-44.
Fujihashi K, Dohi T, Kweon MN, McGhee JR, Koga T, Cooper MD, et al.
Gammadelta T cells regulate mucosally induced tolerance in a dose-dependent fashion. Int Immunol 1999;11:1907-16.
Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X, Benjamin JL, et al.
Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A 2011;108:8743-8.
Simpson SJ, Holländer GA, Mizoguchi E, Allen D, Bhan AK, Wang B, et al.
Expression of pro-inflammatory cytokines by TCR alpha beta+ and TCR gamma delta+ T cells in an experimental model of colitis. Eur J Immunol 1997;27:17-25.
Kawaguchi-Miyashita M, Shimada S, Kurosu H, Kato-Nagaoka N, Matsuoka Y, Ohwaki M, et al.
An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Eur J Immunol 2001;31:980-8.
Mizoguchi A, Mizoguchi E, de Jong YP, Takedatsu H, Preffer FI, Terhorst C, et al.
Role of the CD5 molecule on TCR gammadelta T cell-mediated immune functions: Development of germinal centers and chronic intestinal inflammation. Int Immunol 2003;15:97-108.
Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A. Microfold (M) cells: Important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 2013;6:666-77.
Nochi T, Yuki Y, Matsumura A, Mejima M, Terahara K, Kim DY, et al.
Anovel M cell-specific carbohydrate-targeted mucosal vaccine effectively induces antigen-specific immune responses. J Exp Med 2007;204:2789-96.
Sonnenberg GF, Artis D. Innate lymphoid cell interactions with microbiota: Implications for intestinal health and disease. Immunity 2012;37:601-10.
Lai D, Tang J, Chen L, Fan EK, Scott MJ, Li Y, et al.
Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis. Cell Death Dis 2018;9:369.
Sonnenberg GF, Artis D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 2015;21:698-708.
Fung TC, Bessman NJ, Hepworth MR, Kumar N, Shibata N, Kobuley D, et al.
Lymphoid-tissue-resident commensal bacteria promote members of the IL-10 cytokine family to establish mutualism. Immunity 2016;44:634-46.
Albert-Bayo M, Paracuellos I, González-Castro AM, Rodríguez-Urrutia A, Rodríguez-Lagunas MJ, Alonso-Cotoner C, et al.
Intestinal mucosal mast cells: Key modulators of barrier function and homeostasis. Cells 2019;8. pii: E135.
Poggi A, Benelli R, Venè R, Costa D, Ferrari N, Tosetti F, et al.
Human gut-associated natural killer cells in health and disease. Front Immunol 2019;10:961.
Baker CC, Chaudry IH, Gaines HO, Baue AE. Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model. Surgery 1983;94:331-5.
Chung CS, Watkins L, Funches A, Lomas-Neira J, Cioffi WG, Ayala A. Deficiency of gammadelta T lymphocytes contributes to mortality and immunosuppression in sepsis. Am J Physiol Regul Integr Comp Physiol 2006;291:R1338-43.
Chung CS, Song GY, Wang W, Chaudry IH, Ayala A. Septic mucosal intraepithelial lymphoid immune suppression: Role for nitric oxide not interleukin-10 or transforming growth factor-beta. J Trauma 2000;48:807-12.
Tung JN, Lee WY, Pai MH, Chen WJ, Yeh CL, Yeh SL, et al.
Glutamine modulates CD8αα(+) TCRαβ(+) intestinal intraepithelial lymphocyte expression in mice with polymicrobial sepsis. Nutrition 2013;29:911-7.
Poussier P, Ning T, Banerjee D, Julius M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J Exp Med 2002;195:1491-7.
Inagaki-Ohara K, Dewi FN, Hisaeda H, Smith AL, Jimi F, Miyahira M, et al.
Intestinal intraepithelial lymphocytes sustain the epithelial barrier function against eimeria vermiformis infection. Infect Immun 2006;74:5292-301.
Konjar Š, Frising UC, Ferreira C, Hinterleitner R, Mayassi T, Zhang Q, et al.
Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes. Sci Immunol 2018;3. pii: eaan2543.
Nüssler NC, Stange B, Nussler AK, Settmacher U, Langrehr JM, Neuhaus P, et al.
Upregulation of intraepithelial lymphocyte (IEL) function in the small intestinal mucosa in sepsis. Shock 2001;16:454-8.
Chun TT, Chung CS, Fallon EA, Hutchins NA, Clarke E, Rossi AL, et al.
Group 2 innate lymphoid cells (ILC2s) are key mediators of the inflammatory response in polymicrobial sepsis. Am J Pathol 2018;188:2097-108.
Alverdy JC, Krezalek MA. Collapse of the microbiome, emergence of the pathobiome, and the immunopathology of sepsis. Crit Care Med 2017;45:337-47.
Yoseph BP, Klingensmith NJ, Liang Z, Breed ER, Burd EM, Mittal R, et al.
Mechanisms of intestinal barrier dysfunction in sepsis. Shock 2016;46:52-9.
Coopersmith CM, Stromberg PE, Dunne WM, Davis CG, Amiot DM 2nd
, Buchman TG, et al.
Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002;287:1716-21.
Meng M, Klingensmith NJ, Liang Z, Lyons JD, Fay KT, Chen CW, et al.
Regulators of intestinal epithelial migration in sepsis. Shock 2019;51:88-96.
Mittal R, Coopersmith CM. Redefining the gut as the motor of critical illness. Trends Mol Med 2014;20:214-23.
Meng M, Klingensmith NJ, Coopersmith CM. New insights into the gut as the driver of critical illness and organ failure. Curr Opin Crit Care 2017;23:143-8.
Fay KT, Ford ML, Coopersmith CM. The intestinal microenvironment in sepsis. Biochim Biophys Acta Mol Basis Dis 2017;1863:2574-83.
Clark JA, Coopersmith CM. Intestinal crosstalk: A new paradigm for understanding the gut as the “motor” of critical illness. Shock 2007;28:384-93.
Badami CD, Senthil M, Caputo FJ, Rupani BJ, Doucet D, Pisarenko V, et al.
Mesenteric lymph duct ligation improves survival in a lethal shock model. Shock 2008;30:680-5.
Reino DC, Pisarenko V, Palange D, Doucet D, Bonitz RP, Lu Q, et al.
Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice. PLoS One 2011;6:e14829.
Wildhaber BE, Yang H, Tazuke Y, Teitelbaum DH. Gene alteration of intestinal intraepithelial lymphocytes with administration of total parenteral nutrition. J Pediatr Surg 2003;38:840-3.
Krezalek MA, Yeh A, Alverdy JC, Morowitz M. Influence of nutrition therapy on the intestinal microbiome. Curr Opin Clin Nutr Metab Care 2017;20:131-7.
Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, et al.
PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 2009;106:6303-8.
Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol 2010;88:233-40.
Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K, et al.
PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care 2010;14:R220.
Chang KC, Burnham CA, Compton SM, Rasche DP, Mazuski RJ, McDonough JS, et al.
Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit Care 2013;17:R85.
Chen CW, Mittal R, Klingensmith NJ, Burd EM, Terhorst C, Martin GS, et al.
Cutting edge: 2B4-mediated coinhibition of CD4+ T cells underlies mortality in experimental sepsis. J Immunol 2017;199:1961-6.
Hotchkiss RS, Colston E, Yende S, Angus DC, Moldawer LL, Crouser ED, et al.
Immune checkpoint inhibition in sepsis: A Phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand 1 antibody (BMS-936559). Crit Care Med 2019;47:632-42.
Wu Y, Chung CS, Chen Y, Monaghan SF, Patel S, Huang X, et al.
Anovel role for programmed cell death receptor ligand-1 (PD-L1) in sepsis-induced intestinal dysfunction. Mol Med 2017;22:830-40.
Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, et al.
IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 2010;184:3768-79.
Shindo Y, Fuchs AG, Davis CG, Eitas T, Unsinger J, Burnham CD, et al.
Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa
pneumonia. J Leukoc Biol 2017;101:543-54.
Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, et al.
Interleukin-7 restores lymphocytes in septic shock: The IRIS-7 randomized clinical trial. JCI Insight 2018;3. pii: 98960.
Krämer B, Goeser F, Lutz P, Glässner A, Boesecke C, Schwarze-Zander C, et al.
Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy. PLoS Pathog 2017;13:e1006373.
Tung JN, Lee WY, Pai MH, Chen WJ, Yeh CL, Yeh SL. Glutamine modulates CD8αα(+) TCRαβ(+) intestinal intraepithelial lymphocyte expression in mice with polymicrobial sepsis. Nutrition 2013;29:911-7.
Nose K, Yang H, Sun X, Nose S, Koga H, Feng Y, et al.
Glutamine prevents total parenteral nutrition-associated changes to intraepithelial lymphocyte phenotype and function: A potential mechanism for the preservation of epithelial barrier function. J Interferon Cytokine Res 2010;30:67-80.
Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, et al.
Arandomized trial of glutamine and antioxidants in critically ill patients. N
Engl J Med 2013;368:1489-97.
Ziegler TR, May AK, Hebbar G, Easley KA, Griffith DP, Dave N, et al.
Efficacy and safety of glutamine-supplemented parenteral nutrition in surgical ICU patients: An American multicenter randomized controlled trial. Ann Surg 2016;263:646-55.