Subsets Of Intraepithelial Lymphocytes Research Articles

Recent advances in celiac disease and refractory celiac disease.

Celiac disease (CeD), defined as gluten-induced enteropathy, is a frequent and largely underdiagnosed disease. Diagnosis relies on the detection of highly specific serum IgA anti-transglutaminase auto-antibodies and on the demonstration of duodenal villous atrophy. Treatment necessitates a strict gluten-free diet, which resolves symptoms and enables histological recovery. However, regular follow-up is necessary to assess mucosal healing, which emerges as an important prognostic factor. Recent work on CeD pathogenesis has highlighted how the cross-talk between gluten-specific CD4 + T cells and interleukin-15 can activate cytotoxic intraepithelial lymphocytes and trigger epithelial lesions. Moreover, acquisition by a subset of intraepithelial lymphocytes of somatic gain-of-function mutations in the JAK-STAT pathway was shown to be a decisive step in the progression toward lymphomas complicating CeD, thus opening new therapeutic perspectives for these rare but life-threatening complications.

Human intraepithelial lymphocytes.

The location of intraepithelial lymphocytes (IEL) between epithelial cells, their effector memory, cytolytic and inflammatory phenotype positions them to kill infected epithelial cells and protect the intestine against pathogens. Human TCRαβ+CD8αβ+ IEL have the dual capacity to recognize modified self via natural killer (NK) receptors (autoreactivity) as well as foreign antigen via the T cell receptor (TCR), which is accomplished in mouse by two cell subsets, the naturally occurring TCRαβ+CD8αα+ and adaptively induced TCRαβ+CD8αβ+ IEL subsets, respectively. The private/oligoclonal nature of the TCR repertoire of both human and mouse IEL suggests local environmental factors dictate the specificity of IEL responses. The line between sensing of foreign antigens and autoreactivity is blurred for IEL in celiac disease, where recognition of stress ligands by induced activating NK receptors in conjunction with inflammatory signals such as IL-15 can result in low-affinity TCR/non-cognate antigen and NK receptor/stress ligand interactions triggering destruction of intestinal epithelial cells.

Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor.

Natural killer gene complex-encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell-mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti-Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8α+ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g-expressing activated DCs during immune responses.

Intraepithelial lymphocytes subsets in different forms of celiac disease.

AimThe enumeration of intraepithelial lymphocytes subsets (total, γδ, and CD3– IELs) by flow cytometry (FCM), named as IEL lymphogram, constitutes a useful tool for celiac disease (CD) diagnosis. The aim of this study was to quantify IELs by FCM and their diagnostic value to differentiate active, silent and potential CD.MethodsProspective study of 60 active and 20 silent CD patients, and 161 controls in which duodenal biopsy and IEL quantification by FCM was performed.ResultsActive and silent CD patients had significant higher levels of both total and γδ IELs than absent CD patients (P < 0.0001 and P < 0.0001, P = 0.012 and P < 0.011; respectively). Active and silent CD patients had significant lower levels of CD3– IELs than absent CD patients (P < 0.047 and P < 0.009, respectively). Moreover, they were lower in silent than in active CD patients (P = 0.002). Changes of IELs subsets were more marked in children than adults active CD. The optimal IEL lymphogram cut off values for active CD diagnosis were: ≥10, ≥15 and ≤9 %, and with better performance characteristics for silent CD: ≥ 11, ≥10 and ≤5 %.ConclusionThe evaluation of IELs subsets by FCM is useful to confirm diagnosis of active and silent CD.

CD8αα TCRαβ Intraepithelial Lymphocytes in the Mouse Gut.

The epithelium of the mouse small intestine harbors an abundant CD8αα(+)TCRαβ(+) intraepithelial lymphocyte (IEL) population. This unique IEL subset is a self-reactive population that requires exposure to self-agonists for selection in the thymus, similarly to other regulatory T cell populations. After leaving the thymus, these cells directly seed the intestinal epithelium, which provides a unique combination of cellular interactions together with cytokines, nutrients, and antigens that guide the lineage-specific differentiation and function of these IELs. For instance, epithelial cells and nearby immune cells secrete a number of cytokines, including interleukin-15 (IL-15), IL-7, and transforming growth factor-β, resulting in an assortment of cellular responses, including activation of master transcription factors, cell proliferation, and cytokine secretion. Recent advances have also highlighted the importance of diet-derived substances and commensal metabolites, such as the aryl hydrocarbon receptor ligands and vitamin D, in controlling the survival and gene expression of CD8αα(+)TCRαβ(+) IELs. Furthermore, these cells function in the epithelium and require constant communication between cells in the form of cell-to-cell contacts. These interactions tune the antigen sensitivity of the TCR and maintain the quiescence of the CD8αα(+)TCRαβ(+) IELs. Finally, we discuss how these cells might contribute to tolerance and immunopathological responses in the gut. Therefore, an increased understanding of CD8αα(+)TCRαβ(+) IELs in the gut will help us understand how these cells participate in immune regulation and protection.

Innate Lymphoid Cells Groups 1 and 3 in the Epithelial Compartment of Functional Human Intestinal Allografts

We examined intraepithelial lymphocytes (IELs) in 213 ileal biopsies from 16 bowel grafts and compared them with 32 biopsies from native intestines. During the first year posttransplantation, grafts exhibited low levels of IELs (percentage of CD103(+) cells) principally due to reduced CD3(+) CD8(+) cells, while CD103(+) CD3(-) cell numbers became significantly higher. Changes in IEL subsets did not correlate with histology results, isolated intestine, or multivisceral transplants, but CD3(-) IELs were significantly higher in patients receiving corticosteroids. Compared with controls, more CD3(-) IELs of the grafts expressed CD56, NKp44, interleukin (IL)-23 receptor, retinoid-related orphan receptor gamma t (RORγt), and CCR6. No difference was observed in granzyme B, and CD3(-) CD127(+) cells were more abundant in native intestines. Ex vivo, and after in vitro activation, CD3(-) IELs in grafts produced significantly more interferon (IFN)-γ and IL-22, and a double IFNγ(+) IL-22(+) population was observed. Epithelial cell-depleted grafts IELs were cytotoxic, whereas this was not observed in controls. In conclusion, different from native intestines, a CD3(-) IEL subset predominates in grafts, showing features of natural killer cells and intraepithelial ILC1 (CD56(+) , NKp44(+) , CCR6(+) , CD127(-) , cytotoxicity, and IFNγ secretion), ILC3 (CD56(+) , NKp44(+) , IL-23R(+) , CCR6(+) , RORγt(+) , and IL-22 secretion), and intermediate ILC1-ILC3 phenotypes (IFNγ(+) IL-22(+) ). Viability of intestinal grafts may depend on the balance among proinflammatory and homeostatic roles of ILC subsets.

GPR18 Controls Reconstitution of Mouse Small Intestine Intraepithelial Lymphocytes following Bone Marrow Transplantation.

Specific G protein coupled receptors (GPRs) regulate the proper positioning, function, and development of immune lineage subsets. Here, we demonstrate that GPR18 regulates the reconstitution of intraepithelial lymphocytes (IELs) of the small intestine following bone marrow transplantation. Through analysis of transcriptional microarray data, we find that GPR18 is highly expressed in IELs, lymphoid progenitors, and mature follicular B cells. To establish the physiological role of this largely uncharacterized GPR, we generated Gpr18-/- mice. Despite high levels of GPR18 expression in specific hematopoietic progenitors, Gpr18-/- mice have no defects in lymphopoiesis or myelopoiesis. Moreover, antibody responses following immunization with hapten-protein conjugates or infection with West Nile virus are normal in Gpr18-/- mice. Steady-state numbers of IELs are also normal in Gpr18-/- mice. However, competitive bone marrow reconstitution experiments demonstrate that GPR18 is cell-intrinsically required for the optimal restoration of small intestine TCRγδ+ and TCRαβ+ CD8αα+ IELs. In contrast, GPR18 is dispensable for the reconstitution of large intestine IELs. Moreover, Gpr18-/- bone marrow reconstitutes small intestine IELs similarly to controls in athymic recipients. Gpr18-/- chimeras show no changes in susceptibility to intestinal insults such as Citrobacter rodentium infections or graft versus host disease. These data reveal highly specific requirements for GPR18 in the development and reconstitution of thymus-derived intestinal IEL subsets in the steady-state and after bone marrow transplantation.

The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease

ObjectiveCoeliac disease (CD), a gluten-induced enteropathy, alters the composition and function of duodenal intraepithelial T cells. The intestine also harbours four types of CD3-negative intraepithelial lymphocytes (IELs) with largely unknown...

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

Intestinal intraepithelial T cells contribute to the regulation of inflammatory responses in the intestine; however, the molecular basis for their development and maintenance is unknown. The aryl hydrocarbon receptor complexes with the aryl hydrocarbon receptor nuclear translocator (ARNT) and senses environmental factors, including gut microbiota. Here, we identify ARNT as a critical regulator of the differentiation of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells. Mice deficient in either ARNT or aryl hydrocarbon receptor show a greater than- eight-fold reduction in the number of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells. The number of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells is increased by treatment with an aryl hydrocarbon receptor agonist in germ-free mice and is decreased by antibiotic treatment. The Arnt-deficient precursors of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells express low amounts of STAT3 and fail to differentiate towards the TCRαβ(+)CD8αα(+) cell fate after IL-15 stimulation, a deficiency that is overcome by overexpression of Stat3. These data demonstrate that the ARNT-STAT3 axis is a critical regulator of TCRαβ(+)CD8αα(+) intestinal intraepithelial T-cell development and differentiation.

Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype

In this multicentre study, we examined 60 cases of Type II enteropathy-associated T-cell lymphoma (EATL) from the Asia-Pacific region by histological review, immunohistochemistry and molecular techniques. Patients were mostly adult males (median age: 58 years, male:female 2.6:1), presenting with abdominal pain (60%), intestinal perforation (40%) and weight loss (28%). None had a history of coeliac disease and the median survival was only 7 months. Histologically, these tumours could be divided into (i) central tumour zone comprising a monotonous population of neoplastic lymphocytes, (ii) peripheral zone featuring stunted villi and morphologically atypical lymphocytes showing epitheliotropism, and (iii) distant mucosa with normal villous architecture and cytologically normal intra-epithelial lymphocytes (IELs). Characterized by extensive nuclear expression of Megakaryocyte-associated tyrosine kinase (MATK) (87%) and usually a CD8(+)CD56(+) (88%) cytotoxic phenotype, there was frequent aberrant expression of CD20 (24%). T-cell receptor (TCR) expression was silent or not evaluable in 40% but of the remainder, there was predominant expression of TCRαβ over TCRγδ (1.6:1). In keeping with the normal ratio of IEL subsets, CD8(+) cases showed predominant CD8αα homodimer expression (77%), regardless of TCR lineage. These tumours constitute a distinct entity from classical EATL, and the pathology may reflect tumour progression from IEL precursors, remnants of which are often seen in the distant mucosa.

Intestinal dendritic cells survey circulatory antigens prior to induction of regulatory CD8α/β T cells (106.2)

Abstract Background: Antigens in the intestine transition from fenestrated capillaries through the lamina propria into the draining lymphatics, but whether or how this process controls mucosal immune responses is unclear. CX3CR1+ DCs are uniquely positioned for the recognition of environmental and circulatory antigens in the lamina propria as they interact with both the epithelium and with the capillary vessel system in the lamina propria. Results: We demonstrate that small intestinal CX3CR1+ dendritic cells (DCs) acquire and process both circulatory and luminal antigens in the lamina propria. Through cross-presentation of antigen, CX3CR1+ DCs induce differentiation of IL-10 secreting CD8α/β T regulatory cells, that is dependent upon Programmed Death ligand 1/2 and its counter-structure PD1 of CD8 T cells. Differentiated CD8+ T regulatory cells represent a subset of intraepithelial lymphocytes (IELs) which express the specific adhesion molecule CD103. The CD8+ Tregs inhibit antigen specific CD4+ T cell activation through IL-10 secretion and prevent CD45RBhigh CD4 T cell-mediated small intestinal inflammation. Conclusion: Our finding shows that the lamina propria CX3CR1+ DCs facilitate the surveillance of circulatory antigens and act as a conduit for the processing of self- and intestinally- absorbed antigens leading to the induction of CD8+T regulatory cells, which govern tolerance in the mucosal immune system.

Age-dependent changes in intraepithelial lymphocytes (IELs) of the small intestine, cecum, and colon from young adult to aged mice

We previously reported the regional differences in the IELs present in the proximal (P), middle (M), and distal (D) parts of the small intestine, cecum (Ce), and colon (Co) of mice. In this study, we investigated the age-dependent changes in the regional differences of IELs from young adult to aged mice. In this experiment, 3-, 6-, 12-, 18-, and 24-month-old mice were examined. IELs were separately isolated from 5 parts of the intestines and analyzed by flow cytometry. Regional differences in the number and phenotype of IELs showed the same trends in all age groups. The number of IELs was highest in 6-month-old mice and then gradually decreased with age. As to IEL subsets, age-related changes were not seen except for a few subsets among the age groups. We conclude that age-related decreases in IELs in mouse small intestine may be one of the aging phenomena of the intestinal immune system. Such age-related decreases in IELs may be concerned with the increased liability to intestinal infections in the elderly.

A genomics approach to understand γ/δ T cell function in the gut epithelial compartment. (90.11)

Abstract The gut epithelial functions to provide a protective barrier from enteric pathogens as well as facilitate the absorption and distribution of needed nutrients. These functions are accomplished by the concerted action of a number of interacting cell types including epithelial cells, stromal elements and immune cells. We reason that cells of the immune system are an essential component for the functioning gut epithelia and are likely to play a role in the maintenance of epithelial integrity and function. We have used a genomic-based approach to understand how a novel subset of intraepithelial lymphocytes, γ/δ T cells, contributes to the functioning of the gut epithelial barrier. Using mouse strains deficient for TCR γ/δ, we examined the genes and pathways of the GI tract that are affected by the absence of the TCR γ/δ bearing subset. Our initial analysis revealed that the expression profiles of genes encoding proteins involved in maintaining epithelial integrity and tissue remodeling are regionally and selectively altered in TCR γ/δ deficient mice. In addition, we examined the affect of TCR γ/δ deficiency on the gene sets and pathways activated in the early stages of enteric infection with Salmonella enterica typhimurium. These results reveal abnormal regulation of the acute phase response implying a role for γ/δ T cells in regulating the response to injury. Collectively these studies reveal novel insights into the function of this novel immune cell subset.

Flow Cytometric Analysis of Age-Related Changes in Intestine Intraepithelial Lymphocyte Subsets and Their Functional Preservation After Feeding Mice onSpirulina

We investigated age-related changes in intestinal intraepithelial lymphocyte (IEL) subsets in mice by flow cytometric analysis and their functional preservation as affected by feeding Spirulina, a cyanobacterium that is known to possess various therapeutic effects, including immune modulation activity. The number of cells possessing the leukocyte-common antigen CD45(+) cells in mice (43 weeks old) of the aged group, used as a representative marker for IELs, was significantly lower than that of adult mice (5 weeks old). Either the proportion or the number of CD45(+)CD8(+) cells of the aged mice was significantly lower than that of adult mice, corresponding to previous reports. Proportions and numbers of CD4(+)CD8(+) cells in aged mice, on the other hand, were higher than those in adult mice. Increased or decreased levels of the cell surface antigens observed in the aged mice tended to be restored in aged mice fed Spirulina (aged-SP group), which ingested a hot water extract of Spirulina (SpHW). In fact, the proportions of CD45(+)CD8(+) cells and CD45(+)TCRgammadelta(+) cells in the aged-SP group significantly increased in comparison to the control aged group, which ingested ordinary chow and water ad libitum. These results suggest that ingestion of SpHW in the aged-SP group may contribute to the functional preservation of the intestinal epithelium as a first line of mucosal barrier against infectious agents through retaining the number of certain IELs. Changes in the number of other IEL subsets and blood cells are also discussed.

Enfermedad celíaca del adulto y linfocitos intraepiteliales. ¿Nuevas opciones para el diagnóstico?

Permanent changes have been found in intraepithelial lymphocyte (IEL) subsets in patients with celiac disease. The main aim of this study was to demonstrate the utility of determining CD3()/CD7(+) and T cell receptor (TCR) gamma-delta IEL subsets by flow cytometry as a diagnostic marker of adult celiac disease. We performed a prospective study in a sample of 128 adult patients (70 with celiac disease and 58 controls). In all patients, distal duodenal biopsy was performed and IEL subsets were determined by flow cytometry. Patients with celiac disease showed an increase in gamma-delta IEL subsets and a decrease in CD3(-)/CD7(+) IEL subsets in comparison with the control group, independently of diet. The results indicate that IEL subset determination by flow cytometry could be useful to confirm diagnosis of celiac disease. IEL subsets should be investigated in diseases other than celiac disease, as well as in patients with potential or latent celiac disease.

Generation and homeostatic regulation of CD8αβ effector memory T cells by CD8αα and its ligand, the thymic leukemia (TL) antigen

Abundant intra‐epithelial lymphocytes (IEL) reside within the intestinal epithelium making the intestinal IELs the largest T cell population in the body. The majority of CD8αβ T cell subset of intestinal IELs displays an effector memory phenotype. These experienced T cells populate the mucosal surface and provide rapid and efficient immune protection at the largest entry surface for pathogens. The conditions that lead to mucosal effector memory differentiation are poorly understood. We found that CD8αβ effector memory IELs are derived preferentially from primary effector cells that transiently induce CD8ααduring the effector phase. CD8αα not only plays a key role in this memory differentiation process, but it is also required for long‐term survival of CD8αβ+ effector memory IELs. TL, as a ligand for CD8αα, is not required for the generation or survival of CD8αβ effector memory IELs. Surprisingly however, TL expressed by the intestinal epithelial cells causes death of activated CD8αβ T cells. On the other hand, when interacting with TL, CD8αα rescues activated CD8αβ IEL from cell death induced by TL. Here we provide the first evidence that a unique memory process exists that leads to the specific differentiation of mucosal effector memory T cells that gain the capacity to reside long term at the mucosal surface where they provide immediate and highly effective immune responses upon re‐challenge.

4. Gastrointestinal mucosal immunity

Mucosal surfaces constitute a large host-environmental interface that must be protected from pathogenic organisms. The mucosal immune system has evolved as a distinct immune organ functioning independently from its systemic counterpart. The mucosal immune system has the difficult task of mounting protective responses to invading microorganisms while maintaining a state of nonresponsiveness to commensal bacteria and food antigens. The system has unique cellular components and functional aspects that permit it to carry out this dual role.

Interleukin 2: from immunostimulation to immunoregulation and back again

Interleukin 2 (IL-2) was one of the first cytokines to be discovered. However, the complex role of IL-2 and its receptor in the regulation of immune responses is only now emerging. This review explores the various signals triggered by IL-2 and discusses their translation into biological function. A model is outlined that accommodates the seemingly contradictory functions of IL-2, and explains how one cytokine can be an essential T-cell growth and differentiation factor and yet also be indispensable to maintain peripheral tolerance.

Intraepithelial γδ+ Lymphocytes

Intraepithelial lymphocytes (IELs) phenotyping has emerged as a useful test in intestinal pathology. In celiac disease (CD), a permanent and marked increase of gammadelta+ IELs has been described. However, there is a lack of knowledge about this peculiar IELs population in other intestinal pathologies. To analyze the percentage of IELs, specifically gammadelta+ IELs subset, present in duodenal mucosa biopsies from patients with CD and compare it with those obtained from patients with small intestinal bacterial overgrowth (SIBO) or irritable bowel syndrome (IBS). Twelve patients with untreated CD, 8 patients with SIBO, and 10 patients with diarrhea-predominant IBS were evaluated. All subjects underwent upper endoscopy for mucosal biopsy and jejunal aspirate. From 2 small bowel biopsies, intraepithelial cells were isolated and labeled with the following monoclonal antibodies CD103-PE (phycoerythrin), CD3-FITC (fluoresecein isothio-cynate), CD-7R-PE, CD45RO-APC (allophycocyanin), and TcR gammadelta-FITC. Flow cytometry analysis was performed on a standard FACScan. Total and IELs subset counts were expressed as percentage. Mean total IELs percentage was 16.7+/-6% in IBS, 25.4+/-17% in SIBO, and 26+/-13% in CD patients (P=0.2). CD and SIBO patients, had significantly higher percentages of gammadelta+ IELs (15.7+/-13% and 14.6+/-8%) than IBS subjects (4.1+/-2.5%, P<0.05). There was no difference between CD and SIBO (P=0.6). An increased density of gammadelta+ IELs is typical, but not specific for CD. A similar increase was observed in subjects with SIBO. Our findings suggest that this unique T-cell population might have a key role against intestinal bacterial infections.

Concomitant increase of IL-10 and pro-inflammatory cytokines in intraepithelial lymphocyte subsets in celiac disease

Celiac disease (CD) is a small intestinal enteropathy caused by permanent intolerance to wheat gluten. Active disease is characterized by a prominent cytokine response of intraepithelial lymphocytes (IELs) to gluten-containing diet with concomitant increase in expression of pro-inflammatory IFN-gamma and down-regulatory IL-10 without increase in tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-beta1 (TGF-beta1). The aim was to understand the local immune reaction by determining which intraepithelial T cell subsets produce the different cytokines. The three major IEL-subsets gammadeltaIELs, CD4(+)alphabetaIELs and CD8(+)alphabetaIELs, as well as CD94(+)CD8(+)alphabetaIELs, selectively expanded in active CD, were retrieved from small intestinal biopsies of children with active CD and controls and analyzed quantitatively for cytokine mRNA expression. In active CD, CD8(+)alphabetaIELs showed a significant increase in expression levels of both IFN-gamma and IL-10. CD8(+)alphabetaIELs were also the IEL subset with highest expression level per cell of both cytokines and constituted the cellular source for almost all IFN-gamma and most IL-10. Expression levels of both cytokines were higher in CD94(-)CD8(+)alphabetaIELs than CD94(+)CD8(+)alphabetaIELs. TNF-alpha levels were only increased in CD4(+)alphabetaIELs, which also showed the highest expression level per cell and constituted the major source of this cytokine. Interestingly, IL-10 was increased also in CD4(+)alphabetaIELs. Cytokine levels were low in gammadeltaIELs. 'Classical' CD94(-)CD8(+)alphabeta T cells within the epithelium are responsible for the excessive production of IFN-gamma, believed to drive the formation of intestinal lesions in active CD. Production of IL-10 may be a common feature of IELs producing pro-inflammatory cytokines, thereby attempting to limit inflammation in an autocrine fashion.