Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Weaver, Lehn K.; Minichino, Danielle; Biswas, Chhanda; Chu, Niansheng; Lee, Jung‐Jin; Bittinger, Kyle; Albeituni, Sabrin; Nichols, Kim E.; Behrens, Edward M.

doi:10.1172/jci.insight.124370

Cited by 47 publications

(33 citation statements)

References 57 publications

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“…A recent report by Huggins, et al, noted changes in the CLP model in laboratory mice co-housed with pet store mice (17). The results were modulated by Toll-like receptor (TLR) -4 and were associated with diversification of the microbiome, consistent with findings reported by others under different experimental conditions (18)(19)(20)(21)(22). As in the findings reported here, CLP-induced mortality and serum cytokine levels increased in co-housed mice, as did IFNg production by T cells in response to Listeria infection.…”

Section: Discussionsupporting

confidence: 80%

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

et al. 2020

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The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6 mice with an anti-CD3ϵ activating antibody, a process we term “immune education.” These mice were subjected to the cecal ligation and puncture (CLP) model of sepsis and responses were compared to those of isotype-treated controls. CLP-induced increases in 1) CD4 T cell production and serum levels of IFNγ, 2) CD8 T cell granzyme B levels, and 3) innate cell function were all more pronounced in educated mice than in control mice. Immune education increased CLP-induced liver injury and decreased survival. The differences in responses to CLP were not recapitulated in mice with either isolated CD4 or isolated CD8 T cell memory. Relative to controls, CLP in educated CD8−/− mice (isolated CD4 memory) increased monocyte-derived dendritic cells. Combined CD4 and CD8 memory did not increase monocyte-derived dendritic cells; this combination recapitulated increases in neutrophil and inflammatory monocyte numbers in educated wild-type mice. Induction of T cell memory prior to CLP alters immune responses, organ function, and survival. Both CD4 and CD8 memory T cells play important and independent roles in this response. These findings have profound implications for the development of murine models of human inflammatory disorders such as infection and sepsis.

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Section: Discussionsupporting

confidence: 80%

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

et al. 2020

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“…As for regulation of central myelopoiesis by intestinal microbiota, the absence of microbiota affects myelopoiesis in the BM (Weaver et al, 2019). Mice subjected to either antibiotic treatment or germ-free housing produce significantly fewer GMPs and MDPs in their BM and fewer MDPs and cMOPs in their spleen.…”

Section: Homeostatic Modulators Of Myelopoiesismentioning

confidence: 99%

Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

2019

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Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single cell RNA-sequencing, have highlighted the heterogeneity of the hematopoietic system and revealed new concepts in myeloid cell ontogeny. These technologies are also shedding light on mechanisms of myelopoiesis at homeostasis and at different phases of infection and inflammation, illustrating important feedback loops between affected tissues and the bone marrow. We review these findings here and revisit principles in myelopoiesis in light of the evolving understanding of myeloid cell ontogeny and heterogeneity. We argue for the importance of system-wide evaluation of changes in myelopoiesis and discuss how even after the resolution of inflammation, long-lasting alterations in myelopoiesis may play a role in innate immune memory or trained immunity.

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“…The resulting activation of the immune system due to pathogenic gut microbes results in a nonproductive innate immune response, as well as suppression of the adaptive immune response. There are several ways in which the microbiota influences this pathogenic immune process [7] , [8] , [9] , [10] . Germ free animals have defective immune systems and the gut microbiota influences pathogen dissemination, inflammation, organ damage and mortality in murine pneumonia [9] .…”

mentioning

confidence: 99%

“…Changes in diet with aging may well influence short chain fatty acid production, affecting immune homeostasis, barrier function and severity of COVID-19. Also, commensal microbiota modulates interferon production in the lung and it has been demonstrated that the microbiota influence TLR- augmented immune responses in a mouse model of the cytokine storm [10] . Recent studies showed that nearly 50% of the general population have a T-cell response to SARS-CoV-2 due to cross-reactivity to common cold viruses, thus explaining large numbers of asymptomatic carriers of the virus[ 11 , 12 ].…”

mentioning

confidence: 99%

The role for the metagenome in the pathogenesis of COVID-19

Friedland

Haribabu

2020

EBioMedicine

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Microbiota-dependent signals are required to sustain TLR-mediated immune responses

Cited by 47 publications

References 57 publications

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

The role for the metagenome in the pathogenesis of COVID-19

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