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.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$220,562
Indirect Cost
City
State
Country
Zip Code
Wohlfert, Elizabeth A; Carpenter, Andrea C; Belkaid, Yasmine et al. (2016) In Vitro Analyses of T Cell Effector Differentiation. Methods Mol Biol 1323:117-28
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
Edwards, Justin P; Hand, Timothy W; Morais da Fonseca, Denise et al. (2016) The GARP/Latent TGF-β1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance. Eur J Immunol 46:1480-9
Rodriguez-Peña, A B; Gomez-Rodriguez, J; Kortum, R L et al. (2015) Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules. Gene Ther :
Askenase, Michael H; Han, Seong-Ji; Byrd, Allyson L et al. (2015) Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function during Infection. Immunity 42:1130-42
McCartney-Francis, Nancy; Jin, Wenwen; Belkaid, Yasmine et al. (2014) Aberrant host defense against Leishmania major in the absence of SLPI. J Leukoc Biol :
Yagi, Ryoji; Zhong, Chao; Northrup, Daniel L et al. (2014) The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40:378-88
Mortha, Arthur; Chudnovskiy, Aleksey; Hashimoto, Daigo et al. (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288
Gros, Philippe; Belkaid, Yasmine (2014) Editorial overview: Host pathogens. Curr Opin Immunol 29:iv-vi
Belkaid, Yasmine (2014) Tailored immunity at mucosae. Immunol Rev 260:5-7

Showing the most recent 10 out of 31 publications