Intestinal Lymphoid Organs Research Articles

Herpes simplex Virus Pneumonitis in an Acute/Subacute Paracoccidioidomycosis Patient With Malabsorption Syndrome. Case-Report and Literature Review.

Paracoccidioides sp.-Herpes simplex virus (HSV) co-infection was not reported until now and malabsorption syndrome is a rare complication of the acute/subacute form (AF) of paracoccidioidomycosis (PCM), characterized by life-threatening abnormalities, such as fat and protein loss, lymphopenia, ascites, and intense immunosuppression. A 21-year-old woman presented the PCM AF with intense involvement of the abdominal and intestinal lymphoid organs, which leads to the malabsorption syndrome and severe immunosuppression. This patient developed a fatal-disseminated HSV infection associated with the paracoccidioidal disease. This case demonstrates that, in addition to the antigen-specific immunosuppression, some PCM patients can present a generalized cell-mediated immune depression and endogenous infection of latent microorganisms. On the best of our knowledge, this is the first report of an association between PCM and HSV infection.

Abstract 1914: Orally available oncolytic reovirus, RC402, effectively promotes anti-cancer immunity and synergizes with immune checkpoint blockade in colon cancer

Abstract Introduction: Reoviruses are replication-competent and selectively infect and destroy cancer cells. Although the most common route of oncolytic virotherapy is intratumoral or intravenous administration, these routes are often not clinically feasible because of tumor inaccessibility, tumor multiplicity, and systemic toxicities. Here, we developed an orally available oncolytic reovirus, RC402, to elicit potent anti-tumor immune responses without the above mentioned limitations and thereby maximize the efficacy of PD-1 immune checkpoint blockade in colon cancer. Method: MC38 or CT26 colon cancer-bearing immunocompetent mice were treated with RC402 and/or anti-PD-1 antibody. Tumor growth was monitored after treatment and comprehensively analyzed by flow cytometry and/or multiplex tissue imaging. Results: RC402 treatment effectively delayed tumor growth regardless of the route of administration (per os as well as intratumorally). In particular, orally administered RC402 was well tolerated without gross toxicity and interacted with intestinal immune cells, eliciting adaptive T cell responses within intestinal lymphoid organs such as Peyer's patch. Most of the RC402 was cleared in the gastrointestinal tract within 10 days of the first treatment, and it was not detectable in the blood stream or major organs after oral administration. However, RC402 selectively induced strong and durable anti-tumor immunity in distant tumor tissues. Oral RC402 monotherapy markedly increased CD8+ cytotoxic T cells and decreased CD4+CD25+Foxp3+ regulatory T cells in distant colon cancers, while there were no significant changes in tumor-associated myeloid cells. Finally, oral RC402 treatment cooperated with anti-PD-1 blockade to further suppress colon cancer growth and augment anti-tumor immunity within the tumor microenvironment, leading to complete regression of tumors and survival benefit of tumor-bearing mice. Conclusion: Our study demonstrates that orally available oncolytic reovirus, RC402, could induce potent anti-cancer immune responses and effectively suppress colon cancer progression in combination with anti-PD-1 blockade. Citation Format: Chan Kim, Hong Jae Chon, Hye Jin Lee, Won Suk Lee, Hannah Yang, Jeong Hun Kim, So Jung Kong, Yu Seong Lee, Seung Joon Lee, Enkhtaivan Gansukh, Ki-Hoon Song, Yeon-Sook Lee, Beodeul Kang. Orally available oncolytic reovirus, RC402, effectively promotes anti-cancer immunity and synergizes with immune checkpoint blockade in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1914.

Myeloid Cell Expression of LACC1 Is Required for Bacterial Clearance and Control of Intestinal Inflammation

Loss-of-function variants in the laccase domain containing 1 (LACC1) gene are associated with immune-mediated diseases, including inflammatory bowel disease. It is not clear how LACC1 balances defenses against intestinal bacteria vs intestinal inflammation or what cells are responsible for this balance in humans or mice. Lacc1-/- mice and mice with myeloid-specific disruption of Lacc1 (Lacc1Δmye) were given oral Salmonella Typhimurium or dextran sodium sulfate. CD45RBhiCD4+T cells were transferred to Lacc1-/-Rag2-/- mice to induce colitis. Organs were collected and analyzed by histology and protein expression. Bone marrow-derived macrophages and dendritic cells, lamina propria macrophages, and mesenteric lymph node dendritic cells were examined. We performed assays to measure intestinal permeability, cell subsets, bacterial uptake and clearance, reactive oxygen species, nitrite production, autophagy, signaling, messenger RNA, and cytokine levels. Lacc1-/- mice developed more severe T-cell transfer colitis than wild-type mice and had an increased burden of bacteria in intestinal lymphoid organs, which expressed lower levels of T helper (Th) 1 and Th17 cytokines and higher levels of Th2 cytokines. Intestinal lymphoid organs from mice with deletion of LACC1 had an increased burden of bacteria after oral administration of S Typhimurium and after administration of dextran sodium sulfate compared with wild-type mice. In macrophages, expression of LACC1 was required for toll-like receptor-induced uptake of bacteria, which required PDK1, and of mitogen-activated protein kinase (MAPK)- and nuclear factor κB-dependent induction of reactive oxygen species, reactive nitrogen species, and autophagy. Expression of LACC1 by dendritic cells was required for increasing expression of Th1 and Th17 cytokines and reducing expression of Th2 cytokines upon coculture with CD4+ T cells. Mice with LACC1-deficient myeloid cells had an increased burden of bacteria and altered T-cell cytokines in intestinal lymphoid organs, similar to Lacc1-/- mice. Complementation of cytokines produced by myeloid cells to cocultures of LACC1-deficient myeloid cells and wild-type CD4+ T cells restored T-cell cytokine regulation. When S Typhimurium-infected Lacc1Δmye mice were injected with these myeloid cell-derived cytokines, intestinal tissues increased production of Th1 and Th17 cytokines, and bacteria were reduced. Disruption of Lacc1 in mice increases the burden of bacteria in intestinal lymphoid organs and intestinal inflammation after induction of chronic colitis. LACC1 expression by myeloid cells in mice is required to clear bacteria and to regulate adaptive T-cell responses against microbes.

T cell help to B cells: Cognate and atypical interactions in peripheral and intestinal lymphoid tissues.

Enduring immunity against harmful pathogens depends on the generation of immunological memory. Serum immunoglobulins are constantly secreted by long-lived antibody-producing cells, which provide extended protection from recurrent exposures. These cells originate mainly from germinal center structures, wherein B cells introduce mutations to their immunoglobulin genes followed by affinity-based selection. Generation of high-affinity antibodies relies on physical contacts between T and B cells, a process that facilitates the delivery of fate decision signals. T-B cellular engagements are mediated through interactions between the T cell receptor and its cognate peptide presented on B cell major histocompatibility class II molecules. Here, we describe the cellular and molecular aspects of these cognate T-B interactions, and highlight exceptional cases, especially those arising at intestinal lymphoid organs, at which T cells provide help to B cells in an atypical manner, independent of T cell specificity.

Selective Accumulation of Pro-Inflammatory T Cells in the Intestine Contributes to the Resistance to Autoimmune Demyelinating Disease

Myelin-specific, pro-inflammatory TH17 cells are widely regarded as the drivers of experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively. However, how these harmful autoreactive cells are controlled in vivo remains unclear. By comparing TCR transgenic mice on a disease susceptible and a disease resistant genetic background, we show here that pathogenic TH17 cells are sequestered within the intestine of spontaneous EAE resistant B10.S mice. Disease resistant B10.S mice harbored higher frequencies of TH17 cells in the intestine compared to EAE susceptible SJL/J mice. Moreover, transferred TH17 cells selectively migrated to intestinal lymphoid organs of B10.S mice. The sequestration of TH17 cells in the gut was partially dependent on the gut homing receptor α4β7-mediated adhesion to the intestine. Administration of α4β7 blocking-antibodies increased the peripheral availability of TH17 cells, resulting in increased EAE severity after immunization in B10.S mice. Together, these results support the concept that the intestine is a check-point for controlling pathogenic, organ-specific T cells.

Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice

AbstractEarly in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN–dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8+ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8+ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-beta and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8+ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8+ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/memory CD8+ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1+ expressing cells. Finally, we provide evidence that abrogation of TGF-beta in vitro enhances T-cell proliferation and reduces CD8+ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS.

Ingestion of heat‐treated Lactobacillus rhamnosus GG prevents development of atopic dermatitis in NC/Nga mice

Continuous oral administration of live Lactobacillus rhamnosus GG (L. GG) to pregnant subjects with atopic dermatitis and their children, suppressed the frequency of atopic dermatitis. The details of mechanisms and immune systems involved in this suppressive effect, however, remain speculative. We sought to clarify suppressive mechanisms of L. GG on atopic dermatitis by using NC/Nga mice, a model of human atopic dermatitis. Maternal mice and infant mice were fed with food containing or not containing heat-treated L. GG during pregnancy and breastfeeding, and after weaning. Control NC/Nga mice raised under an air-uncontrolled condition spontaneously manifested typical skin lesions very similar to those in patients with atopic dermatitis. On the other hand, administration of food containing heat-treated L. GG inhibited the onset and development of atopic skin lesions, accompanied by smaller numbers of mast cells and eosinophils in the affected skin sites. Mice fed with L. GG showed a significant increase in plasma IL-10 levels compared with control mice, while there was no significant difference in the proportion of splenic CD4(+)CD25(+) regulatory T cells between mice fed with L. GG and control mice. The IL-10 mRNA expression was enhanced in both Peyer's patches and mesenteric lymph nodes in mice fed with L. GG. These findings suggest that some components of heat-treated L. GG may have an ability to delay the onset and suppress the development of atopic dermatitis, probably through a strong induction of IL-10 in intestinal lymphoid organs and systemic levels.

Role of Lymphotoxins in the Development of Peyer's Patches and Mesenteric Lymph Nodes

Hallmarks of the adaptive immune system are antigen-specific cellular and humoral immune responses. Secondary lymphoid organs serve as sites of contact between antigen-presenting cells (APCs) and immune effector T and B lymphocytes. The gut-associated lymphatic system (GALT) as the intestinal branch of the immune system provides different mechanisms to protect organisms against pathogens. Simultaneously, immune activation secondary to genetic factors and/or environmental signals can induce detrimental autoimmunity. The effector pathways in host defense and autoimmunity use similar cytokines and chemokines. Unlike few other cytokines, lymphotoxin (LT) alpha/beta regulates the development of intestinal lymphoid organs, including Peyer's patches (PPs) and mesenteric lymph nodes (MLNs). In addition, intestinal inflammation is suppressed by inhibition of LTbeta signalling, an observation which has initiated clinical studies using this treatment principle. Conversely, the course of Citrobacter rodentium-induced infectious colitis is more severe in mice with impaired LTbeta-receptor-mediated signalling. This report provides an overview on the role of the different organs of the GALT in intestinal inflammation. Moreover, it describes the role of the LTbeta-receptor-mediated signalling in intestinal inflammation as encountered in autoimmune and infectious pathology. The contribution of LT to the delicate balance of immune effector functions in host defense and autoimmunity is discussed.

Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues.

Effector and memory T cells can be subdivided based on their ability to traffic through peripheral tissues such as inflamed skin and intestinal lamina propria, a property controlled by expression of ‘tissue-specific’ adhesion and chemoattractant receptors. However, little is known about the development of these selectively homing T cell subsets, and it is unclear whether activation in cutaneous versus intestinal lymphoid organs directly results in effector/memory T cells that differentially express adhesion and chemoattracant receptors targeting them to the corresponding nonlymphoid site. We define two murine CD4+ effector/memory T cell subsets that preferentially localize in cutaneous or intestinal lymphoid organs by their reciprocal expression of the adhesion molecules P-selectin ligand (P-lig) and α4β7, respectively. We show that within 2 d of systemic immunization CD4+ T cells activated in cutaneous lymph nodes upregulate P-lig, and downregulate α4β7, while those responding to antigen in intestinal lymph nodes selectively express high levels of α4β7 and acquire responsiveness to the intestinal chemokine thymus-expressed chemokine (TECK). Thus, during an immune response, local microenvironments within cutaneous and intestinal secondary lymphoid organs differentially direct T cell expression of these adhesion and chemoattractant receptors, targeting the resulting effector T cells to the inflamed skin or intestinal lamina propria.

Tissue distribution of IgA receptor-bearing cells in mouse and guinea pig with special reference to the lymphoid population of the gastrointestinal tract

The presence and relative number of cells bearing IgA and IgG receptors in various mouse and guinea pig lymphoid tissues was determined using rosetting techniques. Both types of cells were found to be widely distributed, with cells binding IgG (range 10 to 45%) being more common than cells binding IgA (range 2 to 6%) in all tissues examined. In the mouse, cells bearing IgA receptors were not more prevalent in the intestinal lymphoid organs, Peyer's patches and mesenteric lymph nodes, as compared to the systemic lymphoid organs, spleen and peripheral lymph nodes, although PP contained the highest percentage. In addition, the percentage of cells with IgA or IgG receptors in a given murine tissue did not directly correlate with the capacity of lymphocytes from that tissue to synthesize immunoglobulin of the same isotype upon LPS stimulation. In the guinea pig, cells with IgA receptors were found in both lamina propria and intraepithelial lymphocyte populations isolated from small intestinal mucosa. However, their number there was only marginally higher than that found in other guinea pig tissues, such as spleen. Thus, cells bearing IgA receptors are not preferentially localized in tissues which are active in the secretory (IgA) immune system.