Compartmentalized gut lymph node drainage dictates adaptive immune responses

Esterházy, Daria; Canesso, Maria Cecília Campos; Mesin, Luka; Müller, Paul; Castro, Tiago B. R.; Lockhart, Ainsley; Eljalby, Mahmoud; Faria, Ana Maria Caetano; Mucida, Daniel

doi:10.1038/s41586-019-1125-3

Cited by 230 publications

(235 citation statements)

References 25 publications

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“…To further investigate whether gut immune homeostasis was altered in NOD mice, we analyzed the frequency of CD4 + FoxP3 + Tregs in compartmentalized mLNs and also induction of oral tolerance in these mice. Recently it has been demonstrated that generation of Treg cells in the duodenum draining lymph node is important for oral tolerance induction . We found that frequencies of CD4 + FoxP3 + Treg cells were reduced in duodenum and jejunum draining lymph nodes in prediabetic and diabetic NOD mice and in cecal lymph node of prediabetic mice (Fig.…”

Section: Resultsmentioning

confidence: 53%

“…Recently it has been demonstrated that generation of Treg cells in the duodenum draining lymph node is important for oral tolerance induction. 40 We found that frequencies of CD4 + FoxP3 + Treg cells were reduced in duodenum and jejunum draining lymph nodes in prediabetic and diabetic NOD mice and in cecal lymph node of prediabetic mice (Fig. 7A).…”

Section: Oral Tolerance Was Abrogated In Nod Mice At Early Agementioning

confidence: 81%

“…Failure to maintain such equilibrium may lead to deleterious consequences for intestinal and systemic homeostasis. Among the mLNs, the duodenal lymph node has been characterized as the privileged site to where tolerogenic DCs migrated to induce Tregs and oral tolerance . Interestingly, the duodenal mLN is also identified as pancreatic lymph node suggesting that a lymphatic connection exists between these 2 sites.…”

Section: Discussionmentioning

confidence: 99%

“…12 Compartmentalization of mucosal immune responses at distinct mLNs draining different segments of the intestine seem to be an efficient way to achieve this task. 40 Failure to maintain such equilibrium may lead to deleterious consequences for intestinal and systemic homeostasis. Among the mLNs, the duodenal lymph node has been characterized as the privileged site to where tolerogenic DCs migrated to induce Tregs and oral tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 The local gut lymphatics are linked via afferent lymphatics in the mesentery to the mLNs, which provide a physical route for immune cells that support simultaneously tolerance and protective immune responses through compartmentalization of mLN drainage of the gut segments. 40 To investigate a putative alteration in mucosal DCs in NOD mice, we examined the major DC populations in the mLNs, that include the 2 major populations of migratory mucosal DCs CD103 + CD11band CD103 + CD11b + DCs, as well as CD103+CD11bresident DCs, and CD103 -CD11b + cells that contain both migratory and resident DC populations, as well as possibly CD11c + inflammatory M s derived from the blood monocytes in the mLN, as occurs in models of experimental colitis. The 2 major migratory CD103 + DC populations are highly represented in mLNs, and have been shown to generate Tregs in the steady-state.…”

Section: Alterations In Frequencies Of Mucosal Dcs Were Detected In Mmentioning

confidence: 99%

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Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

Miranda

Oliveira

Torres

et al. 2019

Journal of Leukocyte Biology

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Alterations in the composition of the intestinal microbiota have been associated with development of type 1 diabetes (T1D), but little is known about changes in intestinal homeostasis that contribute to disease pathogenesis. Here, we analyzed oral tolerance induction, components of the intestinal barrier, fecal microbiota, and immune cell phenotypes in non‐obese diabetic (NOD) mice during disease progression compared to non‐obese diabetes resistant (NOR) mice. NOD mice failed to develop oral tolerance and had defective protective/regulatory mechanisms in the intestinal mucosa, including decreased numbers of goblet cells, diminished mucus production, and lower levels of total and bacteria‐bound secretory IgA, as well as an altered IEL profile. These disturbances correlated with bacteria translocation to the pancreatic lymph node possibly contributing to T1D onset. The composition of the fecal microbiota was altered in pre‐diabetic NOD mice, and cross‐fostering of NOD mice by NOR mothers corrected their defect in mucus production, indicating a role for NOD microbiota in gut barrier dysfunction. NOD mice had a reduction of CD103+ dendritic cells (DCs) in the MLNs, together with an increase of effector Th17 cells and ILC3, as well as a decrease of Th2 cells, ILC2, and Treg cells in the small intestine. Importantly, most of these gut alterations precede the onset of insulitis. Disorders in the intestinal mucosa of NOD mice can potentially interfere with the development of T1D due the close relationship between the gut and the pancreas. Understanding these early alterations is important for the design of novel therapeutic strategies for T1D prevention.

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Section: Resultsmentioning

confidence: 53%

Section: Oral Tolerance Was Abrogated In Nod Mice At Early Agementioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Alterations In Frequencies Of Mucosal Dcs Were Detected In Mmentioning

confidence: 99%

See 3 more Smart Citations

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

Miranda

Oliveira

Torres

et al. 2019

Journal of Leukocyte Biology

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Biomaterial Approaches for Understanding and Overcoming Immunological Barriers to Effective Oral Vaccinations

Frizzell

Woodrow

2020

Adv Funct Materials

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Oral vaccines have the potential to reduce cost, improve compliance, and induce immunity at mucosal surfaces that are the first line of defense against infection. The gastrointestinal tract is highly evolved to efficiently digest and absorb nutrients without eliciting aberrant inflammation. However, these functions also limit the efficacy of immunization by the oral route. While mechanisms responsible for the development of tolerance to fed antigens are being illuminated, the application of materials with precise physiochemical properties and immunomodulatory potential may accelerate understanding of immunity within the gastrointestinal tract. Insight into these immunological mechanisms can inform the design of next‐generation oral vaccines to harness critical functions to elicit immunity. Here, material strategies for oral vaccines and their dual function in understanding and overcoming immunological barriers associated with oral immunization are discussed.

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Plasmacytoid dendritic cells regulate host immune response to Citrobacter rodentium induced colitis in colon‐draining lymph nodes

et al. 2020

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Dendritic cells (DCs) are first in line to sense invading microbes and to deliver signals to other immune cells. Plasmacytoid DCs (pDC) produce high amounts of type I interferons (IFNs) but also regulate immune responses. Using the Clec4C (BDCA2)‐diphtheria toxin receptor mouse model allowing conditional pDC depletion, we identified an essential role for pDCs in regulating intestinal inflammation locally in the gut. In pDC‐depleted mice, Citrobacter rodentium infection led to enhanced activation of conventional DCs and induction of IFN‐γ‐producing Th1‐cells in colon‐draining lymph nodes, while induction of Foxp3+/CD25+ Treg and IL‐17‐producing Th17 cells was impaired. Concomitantly, F4/80+ macrophages accumulated into the colon lamina propria in excess, and levels of Il‐1β and Tnf transcripts increased and Foxp3+ Treg were fewer. Our results indicate that pDCs control inflammation in the gut during C. rodentium infection and that they have an important immune regulatory role in colon‐draining lymph nodes.

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Compartmentalized gut lymph node drainage dictates adaptive immune responses

Cited by 230 publications

References 25 publications

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

Biomaterial Approaches for Understanding and Overcoming Immunological Barriers to Effective Oral Vaccinations

Plasmacytoid dendritic cells regulate host immune response to Citrobacter rodentium induced colitis in colon‐draining lymph nodes

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