Gut Lamina Propria Research Articles

Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

AbstractMultiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27−IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27−IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27−IgA+ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.

Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice

Vertebrates typically harbor a rich gastrointestinal microbiota, which has coevolved with the host over millennia and is essential for several host physiological functions, in particular maturation of the immune system. Recent studies have highlighted the importance of a single bacterial species, segmented filamentous bacteria (SFB), in inducing a robust T-helper cell type 17 (Th17) population in the small-intestinal lamina propria (SI-LP) of the mouse gut. Consequently, SFB can promote IL-17-dependent immune and autoimmune responses, gut-associated as well as systemic, including inflammatory arthritis and experimental autoimmune encephalomyelitis. Here, we exploit the incomplete penetrance of SFB colonization of NOD mice in our animal facility to explore its impact on the incidence and course of type 1 diabetes in this prototypical, spontaneous model. There was a strong cosegregation of SFB positivity and diabetes protection in females, but not in males, which remained relatively disease-free regardless of the SFB status. In contrast, insulitis did not depend on SFB colonization. SFB-positive, but not SFB-negative, females had a substantial population of Th17 cells in the SI-LP, which was the only significant, repeatable difference in the examined T-cell compartments of the gut, pancreas, or systemic lymphoid tissues. Th17-signature transcripts dominated the very limited SFB-induced molecular changes detected in SI-LP CD4(+) T cells. Thus, a single bacterium, and the gut immune system alterations associated with it, can either promote or protect from autoimmunity in predisposed mouse models, probably reflecting their variable dependence on different Th subsets.

The Genotype of Early-Transmitting HIV gp120s Promotes α4β7 –Reactivity, Revealing α4β7+/CD4+ T cells As Key Targets in Mucosal Transmission

Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α4β7 +/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin- α4β7. High-affinity for integrin α4β7, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α4β7 affinity is mediated by sequences encoded in gp120 V1/V2. α4β7-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α4β7 +/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine.

T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

Recently, we reported that CD40(-/-) mice, exhibiting exclusively T cell-independent IgA class switch recombination (CSR), demonstrated near normal levels of IgA plasma cells in the gut lamina propria (LP), despite the complete lack of germinal centers (GCs). In this study, we have extended our analysis focusing on how to reconcile these findings using flow cytometry and molecular markers for IgA CSR. In agreement with our previous results with small intestinal LP, the colon LP was found to host IgA CSR only when lymphoid follicles were present. Thus, no IgA CSR was observed in the nonorganized colon LP. By contrast, the Peyer's patch (PP) was the dominant IgA CSR site in both CD40(-/-) and wild type (WT) mice, and they both hosted similar levels of mRNA expression for B cell activating factor of the TNF family, a proliferation inducing ligand, and inducible NO synthase, potential switch-factors for IgA. Unexpectedly, we found that PP B cells undergoing IgA CSR were GL7-intermediate. These cells had not undergone somatic hypermutations (SHMs), whereas GL7-high cells in WT PP, which exhibited GCs, were heavily mutated. Moreover, IgA plasma cells in the LP of CD40(-/-) mice demonstrated few mutations in their Ig V regions, whereas WT LP B cells from different sites showed extensive SHMs, which were also clonally related. Therefore, IgA CSR can occur in PP at a stage preceding manifest GC (GL7-intermediate), whereas SHM require GC formations (GL7-high). These findings reconcile that IgA CSR can occur in PP in the absence of GC with the fact that CD40(-/-) mice host near normal levels of IgA plasma cells in the LP.

H.polygyrus infection induces functionally distinct FOXP3+IL-10+ and FOXP3+IL-10- cell subsets in the Lamina propria of mice (87.15)

Abstract Background: Infection with the murine intestinal helminth H. polygyrus (Hp) results in the regulation of inflammation in the gut Lamina propria (Lp) of mice. Infection upregulates FOXP3 expression in Lp T cells, but the effect of Hp infection on various FOXP3+ subgroups and their function in unknown. We hypothesized that Hp infection induces one or more FOXP3+ T cell subgroups and results in enhanced regulation. Method: We distinguished several FOXP3+ subgroups using a dual reporter mouse for FOXP3 and IL-10. Spleen (Sp), mesenteric lymph nodes (MLN), ileum Lp, and colon Lp cells from mice were analyzed by FACS for percentages of FOXP3 and/or IL-10 expressing cells. Subsets were also tested for their ability to regulate Sp cell proliferation. Results: The FOXP3+IL-10- subset is dominant in the Sp and MLN, the FOXP3+IL-10+ dominates in the colon Lp, and the subsets are roughly equal in the ileum Lp of infected and uninfected mice. Hp infection increases FOXP3+IL-10+ cells in ileum and colon Lp cells vs. uninfected mice. We tested the ability of FOXP3+IL-10+ cells to regulate the proliferation of Sp T cells in 48hr cultures. FOXP3+IL-10- inhibited proliferation better than FOXP3+IL-10+ cells (67.41% vs. 23.88% inhibition, 1:1 ratio). Discussion: Hp infection increases FOXP3+IL-10+ expression in the Lp. Other regulatory roles for FOXP3+IL-10+ cells are being investigated and may be important in understanding how Hp infection regulates gut inflammation.

Lack of Retinoic Acid Leads to Increased Langerin-Expressing Dendritic Cells in Gut-Associated Lymphoid Tissues

Retinoic acid (RA) is a crucial factor for maintaining homeostasis in the gut, including lymphocyte homing, immunoglobulin (Ig) A production, and T regulatory cells (Treg) and T helper cell 17 (T(H)17) generation. Until now, most attention has focused on the function of dendritic cells (DCs) to initiate adaptive immunity including T and B lymphocytes through RA. To investigate the effects of RA on DCs of gut-associated lymphoid tissue (GALT), we analyzed the phenotype and function of DC subsets from GALT of vitamin A-deficient (VAD) mice. VAD mice were prepared by feeding them a VAD diet over 12 weeks from gestational days 10-14. Here, we report that tremendous increase of langerin(+) DCs occurred in the mesenteric lymph nodes (MLNs) and gut lamina propria of VAD mice dependent on CCR7 signaling. Langerin(+) DCs have phenotypes more similar to those of bone marrow-derived dermal langerin(+) DCs than epidermal Langerhans cells. Moreover, RA receptor antagonists enhance the differentiation of langerin(+) DCs from mouse and human precursors of bone marrow and peripheral blood. Langerin(+) DCs were highly differentiated but less inflammatory than langerin(-) DCs of MLNs of VAD mice. Moreover, tolerance to orally delivered antigen was completely abrogated by depletion of langerin(+) DCs in the VAD mice. These results suggest that generation of langerin(+) DCs in the GALT is tightly regulated by RA and that the microenvironment of tissues determines the phenotype of DCs.

The Survival of Memory CD4+ T Cells within the Gut Lamina Propria Requires OX40 and CD30 Signals

Although CD4(+) memory T cells reside within secondary lymphoid tissue, the major reservoir of these cells is in the lamina propria of the intestine. In this study, we demonstrate that, in the absence of signals through both OX40 and CD30, CD4(+) T cells are comprehensively depleted from the lamina propria. Deficiency in either CD30 or OX40 alone reduced CD4(+) T cell numbers, however, in mice deficient in both OX40 and CD30, CD4(+) T cell loss was greatly exacerbated. This loss of CD4(+) T cells was not due to a homing defect because CD30 x OX40-deficient OTII cells were not impaired in their ability to express CCR9 and alpha(4)beta(7) or traffic to the small intestine. There was also no difference in the priming of wild-type (WT) and CD30 x OX40-deficient OTII cells in the mesenteric lymph node after oral immunization. However, following oral immunization, CD30 x OX40-deficient OTII cells trafficked to the lamina propria but failed to persist compared with WT OTII cells. This was not due to reduced levels of Bcl-2 or Bcl-XL, because expression of these was comparable between WT and double knockout OTII cells. Collectively, these data demonstrate that signals through CD30 and OX40 are required for the survival of CD4(+) T cells within the small intestine lamina propria.

Role of β7 Integrins in Intestinal Lymphocyte Homing and Retention

Lymphocytes involved in intestinal immune response are found in organized immune inductive sites of the gut-associated lymphoid tissues (GALT) such as Peyer's patches (PP), mesenteric lymph nodes (MLN) and diffuse effector sites of gut epithelium and lamina propria (LP). beta(7) integrins are responsible for efficient trafficking and retention of lymphocytes in these sites. Naïve and effector lymphocytes use alpha(4)beta(7) integrin to extravasate from blood to gut mucosal tissues of GALT, MLN and LP via interactions with Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1). The alpha(E)beta(7) integrin facilitates retention of effector and memory lymphocytes in the gut epithelial layer via interactions with E-cadherin. Mucosal dendritic cells (DCs) regulate the expression of the gut homing receptors alpha(4)beta(7) integrin and the chemokine receptor CCR9 on activated effector and regulatory lymphocytes in a retinoic acid-dependent manner. CD103 (alpha(E) integrin) identifies a subset of mucosal DCs in MLN and small intestine LP that have an enhanced ability to induce gut-tropic receptors on responding lymphocytes. The interactions between beta(7) integrin and their ligands are also implicated in the pathogenesis and progression of inflammatory bowel diseases (IBDs), intestinal parasitic infections and graft-versus-host diseases. During intestinal inflammation, beta(7) integrin-dependent and -independent pathways contribute to lymphocytes recruitment to the intestinal tissues and disease pat-hogenesis. Recent works have explored the potential of therapeutic targeting of alpha(4) and beta(7) integrins in IBDs. Here, we review the current understanding of the role of beta(7) integrins in intestinal lymphocyte trafficking and retention in health and disease.

Before They Were Gut Dendritic Cells

Gut lamina propria dendritic cell (DC) subsets have specialized functions. In this issue of Immunity, Varol et al. (2009) and Bogunovic et al. (2009) describe the different blood precursors for CD103(+) and CD103(-) DC subsets.

CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease

Background Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied. Aim To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD. Methods Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA. Results CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs. Conclusion These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohn's disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.

Human mid‐gestation amniotic fluid contains interleukin‐16 bioactivity

CD4-positive cells are detectable in the human fetal gastrointestinal tract from 11 weeks of gestation. Interleukin-16 (IL-16) is a chemoattractant for CD4(+) cells and, via fetal swallowing of amniotic fluid, could mediate the influx of CD4(+) cells into the fetal gut. We have shown that IL-16 was detectable in human amniotic fluid at 16-18 weeks of gestation (mid-pregnancy) but was not detectable at term (late pregnancy; > 37 weeks of gestation). Similarly, mid-pregnancy, but not late pregnancy, amniotic fluid contained chemotactic activity for CD4(+) T cells, this activity was reduced by 58% in the presence of a neutralizing anti-IL-16 antibody. The levels of IL-16 in fetal plasma at 16-24 weeks of gestation were very high, and decreased significantly by 25-36 weeks but at > 37 weeks remained significantly higher than adult levels. IL-16 transcripts were detectable in whole tissue extracts of fetal gut, skin and placenta but not in amniocytes, and IL-16 immunoreactivity was detectable in cells within the lamina propria of the fetal gut and within the skin, where it was associated with the basement membrane. Neither IL-16 levels nor chemotactic activity for CD4(+) T cells in mid-pregnancy amniotic fluid was related to atopic outcomes at 1 year of age. IL-16 might have an important role in the early development of the human immune system and/or in regulating fetal and maternal immunological responsiveness during pregnancy.

The Gastrointestinal Tract and AIDS Pathogenesis

Gastrointestinal disease has been recognized as a major manifestation of human immunodeficiency virus infection since the earliest recognition of acquired immunodeficiency syndrome (AIDS). Originally, these disease manifestations were considered to be sequelae of the immune destruction that characterizes AIDS rather than being central to the pathogenesis of AIDS. Over time, it has become clear that the mucosal immune system in general and the intestinal immune system in particular are central to the pathogenesis of AIDS, with most of the critical events (eg, transmission, viral amplification, CD4+ T-cell destruction) occurring in the gastrointestinal tract. Compared with peripheral blood, these tissues are not easily accessible for analysis and have only begun to be examined in detail recently. In addition, although the resulting disease can progress over years, many critical events happen within the first few weeks of infection, when most patients are unaware that they are infected. Moreover, breakdown of the mucosal barrier and resulting microbial translocation are believed to be major drivers of AIDS progression. In this review, we focus on the interaction between primate lentiviruses and the gastrointestinal tract and discuss how this interaction promotes the pathogenesis of AIDS and drives immune dysfunction and progression to AIDS. This article draws extensively on work done in the nonhuman primate model of AIDS to fill gaps in our understanding of AIDS in humans.

Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin

NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.

CCR2 Receptor Is Essential to Activate Microbicidal Mechanisms to Control Toxoplasma gondii Infection in the Central Nervous System

Chemokines comprise a structurally related family of cytokines that regulate leukocyte trafficking. Because infection with Toxoplasma gondii can induce an important inflammatory reaction that, if left uncontrolled, can lead to death, we investigated the role of the chemokine receptor CCR2 in T. gondii infection. We orally infected CCR2(-/-) mice with five ME-49 T. gondii cysts and monitored morbidity, survival, and immune response thereafter. The CCR2(-/-) mice displayed higher susceptibility to infection as all mice died on day 28 after infection. Despite similar Th1 responses, a more evident anti-inflammatory response was induced in the peripheral organs of CCR2(-/-) mice compared with wild-type C57BL/6 mice. Additionally, CCR2(-/-) mice presented greater parasitism and a milder inflammatory reaction in their peripheral organs with lesser CD4(+) and MAC-1(+) and greater CD8(+) cell migration. The parasite load decreased in these organs in CCR2(-/-) mice but remained uncontrolled in the central nervous system. Additionally, we observed down-regulated inducible nitric oxide synthase expression in peripheral organs from CCR2(-/-) mice that was associated with a small nitric oxide production by spleen macrophages. In conclusion, in the absence of CCR2, another mechanism is activated to control tissue parasitism in peripheral organs. Nevertheless, CCR2 is essential for the activation of microbicidal mediators that control T. gondii replication in the central nervous system.

MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells

Like CD1d-restricted iNKT cells, mucosal-associated invariant T cells (MAITs) are “innate” T cells that express a canonical TCRα chain, have a memory phenotype, and rapidly secrete cytokines upon TCR ligation. Unlike iNKT cells, MAIT cells require the class Ib molecule MHC-related protein I (MR1), B cells, and gut flora for development and/or expansion, and they preferentially reside in the gut lamina propria. Evidence strongly suggests that MAIT cell activation is ligand-dependent, but the nature of MR1 ligand is unknown. In this study, we define a mechanism of endogenous antigen presentation by MR1 to MAIT cells. MAIT cell activation was dependent neither on a proteasome-processed ligand nor on the chaperoning by the MHC class I peptide loading complex. However, MAIT cell activation was enhanced by overexpression of MHC class II chaperones Ii and DM and was strikingly diminished by silencing endogenous Ii. Furthermore, inhibiting the acidification of the endocytic compartments reduced MR1 surface expression and ablated MAIT cell activation. The importance of the late endosome for MR1 antigen presentation was further corroborated by the localization of MR1 molecules in the multivesicular endosomes. These findings demonstrate that MR1 traffics through endocytic compartments, thereby allowing MAIT cells to sample both endocytosed and endogenous antigens.

Mucosal immunity induced by orally administered transgenic plants

Oral immunization is an efficient means to induce protection at the portal entrance for many pathogens. Therefore, the design of efficient edible vaccines through transgenic plants represents a challenging alternative to the traditional injectable ones. We have previously reported the construction of transgenic potato plants expressing the genes coding for the immunogenic proteins of Newcastle Disease Virus (NDV) and their immunogenicity in mice. All mice receiving transgenic plant extracts in incomplete Freund's adjuvant produced specific antibodies. Animals fed with transgenic leaves also showed a specific response against NDV. The aim of the present study was to continue the evaluation of the mucosal immune response. Adult Balb/c mice were fed with potato leaves for a month and on day 36 mucosal samples were collected. ELISAs performed on intestinal washes showed that transformed plants elicited the synthesis of NDV-specific IgG and IgA antibodies. In addition, anti-NDV IgA antibodies were detected in supernatants of cultured small intestine fragments of mice fed with the recombinant immunogens, suggesting the presence of NDV-specific IgA secreting plasma cells in the intestinal tissue. Moreover, we detected specific anti-NDV antibodies in intestinal fluids after oral immunization with F and HN transgenic plants. Also, indirect immunofluorescence on intestinal tissue was performed. The present results suggest that these immunogens, F and HN glycoproteins of NDV, when orally administered, would enhance the number of IgA + B cells, and the cytotoxic cellular immune response via CD8 + T cells, found in the gut lamina propria that is in accordance with our first findings.

Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response?

Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response?

Salmonella enterica serovar Typhimurium Induces Rapid Migration of Dendritic Cells into the Gut Lumen

Dendritic cells (DC)s are key elements for the immune responses and can operate as antigen sampling cells. We report now that they can also migrate into the gut lumen upon bacterial challenge. Isolated intestinal loops in BALB/c mice, C57/BL6 and C57/BL6 MyD88 knock out (KO) mice were infected with non invasive GFP‐labelled S. Typhimurium strain SL1344 (?SPI1, rpsM‐gfp), a derivative of the same strain lacking SPI1 and both fliC and fljB flagellin encoding genes, E. coli DH5a (/pZEP16, rpsM‐gfp), or PBS. After three hours, luminal content was harvested, washed and DCs were separated. FACS was carried out to characterize and enumerate the recovered cells. Confocal microscopy (CM) and TEM were also performed.Approximately 7 × 104 cells were present in loops treated with flagellated S. typhimurium SL1344, but not in loops belonging to the C57/BL6 MyD88 KO mice. Phenotypic analysis showed the presence of CD11c+, CX3CR1+, MHCII+, CD8a− and CD11b− cells associated with Salmonella. CM confirmed the increase of CD11c+ DCs in the gut lamina propria. TEM and CM showed bacteria associated with luminal DCs. These data show that Salmonella induces flagellin‐ and Toll‐like receptor‐dependent DC migration into the gut lumen.

TGFb and IL2 maintain helminth‐induced FOXP3 expression and increase relative FOXP3 levels in murine gut lamina propria CD8 T cells

Intro: The immune system limits gut inflammation. H. polygyrus is a murine intestinal helminth. In lamina propria (Lp), H. polygyrus infection up‐regulates a marker of Tregs, FOXP3, in CD8+T cells and induces Th2 and regulatory cytokines. This study examined if worm‐induced cytokines enhance FOXP3 expression.Method: Reporter mice, which express a FOXP3‐EGFP fusion protein, were infected with H. polygyrus. After 2 wks, Lp mononuclear cells (LPMC) were isolated. Unfractionated LPMC and FACS sorted EGFP+ and EGFP− T cells were cultured 48hr with or without various cytokines (IL10, TGFb, IL2, IL4). Cells then were stained for CD8 and Thy1.2 and analyzed for FOXP3 expression with FACS. Controls included cells from littermates without worms.Results: In LPMC from worm‐infected mice, TGFb/IL2 together increased FOXP3+CD8+ T cell number and degree of expression: 2.23 ± 0.21, p = 0.002, N = 5 fold increase in number, 1.78 ± 0.18, p = 0.0065, N = 3 fold change in degree of expression. Mesenteric lymph node or spleen cells were unaffected. EGFP− LPMC cultured with TGFb/IL2 did not turn +. EGFP+ cells cultured alone lose FOXP3. TGFb/IL2 added to these cultures maintained FOXP3 expression.Discussion: H. polygyrus infection abrogates colitis. Lp CD8+ T cells limit gut inflammation. TGFb/IL2, induced in the gut by worms, maintain but do not induce high FOXP3 levels in CD8+ Tregs and may promote regulation. (DK38327, 058755, 034928)

Simian Immunodeficiency Virus–Induced Intestinal Cell Apoptosis Is the Underlying Mechanism of the Regenerative Enteropathy of Early Infection

The enteropathic manifestations of the human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) in late infection are usually due to infection by other microbes, but in early infection the viruses themselves cause an enteropathy by heretofore undetermined mechanisms. Here we report that SIV induces massive apoptosis of intestinal epithelial cells lining the small and large bowel, thus identifying apoptosis as the driving force behind the regenerative pathology of early infection. We found that apoptosis of gut epithelium paralleled the previously documented apoptosis and massive depletion of CD4 T cells in gut lamina propria, triggered by established mechanisms of gut epithelial cell apoptosis and, at peak, possibly by virus interactions with GPR15/Bob, an intestinal epithelial cell-associated alternative coreceptor for SIV and HIV-1. Apoptosis in early SIV infection is thus the common theme of the pathological processes that quickly afflict the innate as well as adaptive arms of the gut immune system.