Assessing the Role of CD103 in Immunity to an Intestinal Helminth Parasite

In the intestine, the integrin CD103 is expressed on a subset of T regulatory (T(reg)) cells and a population of dendritic cells (DCs) that produce retinoic acid and promote immune homeostasis. However, the role of CD103 during intestinal helminth infection has not been tested.We demonstrate that CD103 is dispensable for the development of protective immunity to the helminth parasite Trichuris muris. While we observed an increase in the frequency of CD103(+) DCs in the lamina propria (LP) following acute high-dose infection with Trichuris, lack of CD103 had no effect on the frequency of CD11c(+) DCs in the LP or mesenteric lymph nodes (mLN). CD103-deficient (CD103(-/-)) mice develop a slightly increased and earlier T cell response but resolve infection with similar kinetics to control mice. Similarly, low-dose chronic infection of CD103(-/-) mice with Trichuris resulted in no significant difference in immunity or parasite burden. Absence of CD103 also had no effect on the frequency of CD4(+)CD25(+)Foxp3(+) T(reg) cells in the mLN or LP.These results suggest that CD103 is dispensable for intestinal immunity during helminth infection. Furthermore, lack of CD103 had no effect on DC or T(reg) recruitment or retention within the large intestine

Transplantation tolerance: lessons from experimental rodent models

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models

Sex impacts Th1 cells, Tregs, and DCs in both intestinal and systemic immunity in a mouse strain and location-dependent manner

Background: Males and females have a different predisposition for the development of intestinal disorders, like inflammatory bowel disease (IBD). We hypothesized that sex specific differences in intestinal immune responses may underlie this bias. To test this hypothesis, we studied sex differences in immune cell populations in the Peyer's patches (PP). For comparison with systemic immunity, we studied spleen cells. Methods: Two mouse strains with different susceptibility for developing colitis (BALB/c and C57Bl/6) were used. Using flow cytometry, we measured the percentage of T cells, Th1, Th17, and Treg cells in the PP and spleen. In addition, we measured the percentages of NK cells, macrophages, myeloid, and lymphoid dendritic cells (DCs) and their expression of CD80 and CD103. Moreover, we measured percentages of monocyte subsets in the peripheral circulation. Results were tested using two-way ANOVA, p <0.05. Results: Males had a lower percentage of T cells in both PP and spleen (PP BALB/c 22.1 %, B6 13.6 %; spleen BALB/c 4.7 %, B6 19.9 %) but a higher percentage of Th1 cell in both tissues (PP BALB/c 350 %, B6 109.5 %; spleen BALB/c 48.7 %, B6 41.9 %) than females. They also had a higher percentage of Tregs in the spleen than females (BALB/c 20.5 %, B6 4.5 %). Furthermore, males had a higher percentage of CD80(+) DCs in both the PP and spleen (lymphoid DCs in PP BALB/c 104.7 %, B6 29.6 %; spleen BALB/c 72.2 %, B6 44.2 %; myeloid DCs in PP BALB/c 80.5 %, B6 93.3 %; spleen BALB/c 88.5 %, B6 50.8 %) and a higher percentage of lymphoid CD103(+) DCs in the spleen than females (BALB/c 41.5 %, B6 28.3 %). The percentage of NK cells was decreased in the spleen (BALB/c 12.5 %, B6 25.1 %) but increased in the PP (BALB/c 75.7 %, B6 78.6 %) of males as compared with females. Strain differences were also found in the PP; BALB/c mice had a higher percentage of T cells (males 58.1 %, females 75.5 %), a higher Th/Tc ratio (males 81.0 %, females 134.2 %), less FoxP3(+)CD25(-) T cells (males 14.6 %, females 30.0 %), more DCs (males 14.8 %, females 15.7 %) and macrophages (males 67.9 %, females 141.2 %), and more NK cells (males 160 %, females 164.3 %) than BALB/c mice. Conclusions: In this study, we show sex differences in intestinal and peripheral immune populations. These differences may underlie sex differences in intestinal disorders like IBD, and this information may be an important knowledge for the treatment of intestinal-related diseases

TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs

Regulatory T Cells in γ Irradiation-Induced Immune Suppression

Sublethal total body γ irradiation (TBI) of mammals causes generalized immunosuppression, in part by induction of lymphocyte apoptosis. Here, we provide evidence that a part of this immune suppression may be attributable to dysfunction of immune regulation. We investigated the effects of sublethal TBI on T cell memory responses to gain insight into the potential for loss of vaccine immunity following such exposure. We show that in mice primed to an MHC class I alloantigen, the accelerated graft rejection T memory response is specifically lost several weeks following TBI, whereas identically treated naïve mice at the same time point had completely recovered normal rejection kinetics. Depletion in vivo with anti-CD4 or anti-CD25 showed that the mechanism involved cells consistent with a regulatory T cell (T reg) phenotype. The loss of the T memory response following TBI was associated with a relative increase of CD4+CD25+ Foxp3+ expressing T regs, as compared to the CD8+ T effector cells requisite for skin graft rejection. The radiation-induced T memory suppression was shown to be antigen-specific in that a third party ipsilateral graft rejected with normal kinetics. Remarkably, following the eventual rejection of the first MHC class I disparate skin graft, the suppressive environment was maintained, with markedly prolonged survival of a second identical allograft. These findings have potential importance as regards the immunologic status of T memory responses in victims of ionizing radiation exposure and apoptosis-inducing therapies

Compartment-specific immunity in the human gut: Properties and functions of dendritic cells in the colon versus the ileum

© 2015 The Authors. Published by BMJ. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: http://dx.doi.org/10.1136/gutjnl-2014-307916Objective Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC. Design Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction. Results A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-a and interleukin (IL)-1ß) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4+FoxP3+IL-10+ (regulatory) T cells. There were enhanced proportions of CD103+Sirpa- DC in the colon, with increased proportions of CD103+Sirpa+ DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103+Sirpa+ DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103+ DC, in particular CD103+Sirpa+ DC. However, expression of ILT3 was associated with CD103- DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells. Conclusions The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.This research was funded by St. Mark's Foundation (Harrow, UK), The Biotechnology and Biological Sciences Research Council (BBSRC; BB/J004529/1) and The National Institutes of Health (NIH; US) including The National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK; T32-DK07632 and P01-DK072084) and The National Institute of Allergy and Infectious Disease (NIH/NIAID; R21-AI094033). We also gratefully acknowledge funding support from The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Centre at The Johns Hopkins Hospital, Baltimore, US.Published versio

Homeostasis of intestinal immune regulation.

Regulatory CD4 T cells with the capacity to inhibit potentially harmful immune responses have been described in various experimental systems. Although the observations are converging towards the naturally activated CD25(+) CD4 T cells as a major population responsible for this protection, there is still considerable disagreement on the molecular and cellular requirements involved to achieve a stable immune homeostasis in vivo