Maintenance of tolerance and restoration of host homeostasis following insults relies on a complex and coordinated set of innate and adaptive responses. These tissue tailored responses are controlled by specialized populations of cells that integrate local cues such as defined metabolites or cytokines in order to induce responses in a way that preserve the functional requirements of each tissue. Our work helped to identify some of these tissue specific immunological networks and their role in the development of appropriate and controlled immune responses 1- We previously showed that the gut mucosal environment is controlled by a unique subset of DC expressing CD103 with enhanced capacity to present antigen and induce regulatory T cells under steady state conditions. However, during acute infection, both Treg and CD103+DCs disappear from the mucosal environment. How regulation is sustained in these highly reactive mucosal settings is poorly understood. We postulated that, to insure host survival, inflammatory cells accumulating in the infected tissue could develop regulatory properties. Indeed, we found that during acute mucosal infection, Ly6Chi inflammatory monocytes, previously know for their antimicrobial function, acquire a gut specific regulatory phenotype associated with high level of the lipid mediator prostaglandin E2 (PGE2) production. PGE2 production by inflammatory monocytes is associated with their powerful inhibition of neutrophil activation and control of lethality during mucosal acute infection. This work reveals a previously unappreciated role for inflammatory monocytes in the regulation of mucosal responses and place these cells at the center of a commensal driven regulatory loop required to control host-commensal dialogue during inflammation. Because of the role of neutrophils in mediating tissue damages in multiple settings, these finding have important clinical implications. In addition of proposing PGE2 as a mean of limiting mucosal pathology, our work also provide a potential explanation for the GI damages associated with suppression of prostaglandin synthesis by non-steroidal anti-inflammatory drugs (NSAIDs). 2- Inflammation alters hematopoiesis, often by decreasing erythropoiesis and enhancing myeloid output. The mechanisms underlying these changes and how the bone marrow stroma contributes to this process during infection are poorly understood. In collaboration with an expert in the field of stromal cells, Pamela Robey (NIDCR), we found that acute mucosal infection alters early myeloerythroid differentiation, blocking erythroid development while expanding the granulocyte macrophage progenitor population. We found that bone marrow stromal cells regulate these hematopoietic changes via a previously unrecognized capacity to produce IL-6.
| Xu, Mo; Pokrovskii, Maria; Ding, Yi et al. (2018) c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554:373-377 |
| Carpenter, Andrea C; Wohlfert, Elizabeth; Chopp, Laura B et al. (2017) Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF. J Immunol 199:1716-1728 |
| Lu, Ying; Zhang, Xianyu; Bouladoux, Nicolas et al. (2017) Zbtb1 controls NKp46+ ROR-gamma-T+ innate lymphoid cell (ILC3) development. Oncotarget 8:55877-55888 |
| Bouladoux, Nicolas; Harrison, Oliver J; Belkaid, Yasmine (2017) The Mouse Model of Infection with Citrobacter rodentium. Curr Protoc Immunol 119:19.15.1-19.15.25 |
| Han, Seong-Ji; Glatman Zaretsky, Arielle; Andrade-Oliveira, Vinicius et al. (2017) White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection. Immunity 47:1154-1168.e6 |
| Buxbaum, Nataliya P; Farthing, Donald E; Maglakelidze, Natella et al. (2017) In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease. JCI Insight 2: |
| Bouladoux, Nicolas; Hennequin, Clotilde; Malosse, Camille et al. (2017) Hapten-Specific T Cell-Mediated Skin Inflammation: Flow Cytometry Analysis of Mouse Skin Inflammatory Infiltrate. Methods Mol Biol 1559:21-36 |
| Lee, Ha-Na; Tian, Linjie; Bouladoux, Nicolas et al. (2017) Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation. J Clin Invest 127:1905-1917 |
| Hand, Timothy W; Vujkovic-Cvijin, Ivan; Ridaura, Vanessa K et al. (2016) Linking the Microbiota, Chronic Disease, and the Immune System. Trends Endocrinol Metab 27:831-843 |
| Zhong, Chao; Cui, Kairong; Wilhelm, Christoph et al. (2016) Erratum: Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment. Nat Immunol 17:469 |
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