The intestinal immune system must protect the host from pathogenic microorganisms while maintaining a symbiotic relationship with an enormous load of resident microorganisms (the microbiota). It is well recognized that interactions between the intestine, intestinal immune system, and the microbiota are essential for human health. Thus, a number of mechanisms exist to help foster these collaborations. Breakdown of these mechanisms is thought to result in a variety of pathologies, including the development of inflammatory bowel diseases (IBD). Because the microbiota displays the same immunostimulatory molecules as pathogens and can trigger inflammation and disease upon dysregulation, a critical question is how the intestinal immune system mounts protective responses to pathogens while avoiding inflammatory responses against the microbiota.
The main focus of the lab is to understand the cellular and molecular processes limiting inflammation against the microbiota. We focus on CX3CR1 expressing mononuclear phagocyte (MNP), a cell lineage that we believe is critical in regulating homeostasis with the microbiota. MNPs consist of monocytes, dendritic cells (DC), and macrophages, all of which defend against pathogens as well as maintain tissue homeostasis.
We recently demonstrated two ways CX3CR1+ MNPs integrate signals from the microbiota to limit intestinal inflammation and promote mucosal healing. First, recognition of the microbiota limits CX3CR1+ MNP migration from the intestine to the mesenteric lymph node1. We hypothesize that this limits microbiota directed T cell responses. Second, signals from the microbiota induce CX3CR1+ MNPs to promote mucosal barrier function and repair in both mice and humans through the regulation of innate lymphoid cells (ILCs)2. To study the in vivo role of these cells, we generated novel mouse strains in which CX3CR1+ MNPs can be selectively depleted in vivo1, 2. We hypothesize that CX3CR1+ cells normally respond to microbiota-derived signals and maintain intestinal homeostasis by limiting inflammation and promoting barrier function.
The projects in the lab focus on the in vivo role of CX3CR1+ MNPs and how these functions are modulated by the microbiota. These projects include:
1. Identifying cellular pathways within CX3CR1+MNPs critical for maintenance of intestinal homeostasis.
2. Characterizing the role of CX3CR1+MNPs in the control of intestinal T cell responses
3. Characterizing the regulation of CX3CR1+MNP function by distinct microbial species.
Diehl GE, Longman RS, Zhang JX, et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1+ cells. Nature 2013;494:116-20.
Longman RS, Diehl GE, Victorio DA, et al. CX(3)CR1(+) mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med 2014;211:1571-83.