Tissue-Specific Immune Cell Networks
Mucosal barrier sites pose a particular challenge for the immune system. These barriers, such as the Gastrointestinal (GI) tract and Oral mucosa, are sites of frequent pathogen invasion but also home to diverse commensal microbial communities. As such, the immune system must be carefully tailored to the tissue microenvironment to limit aberrant responses to commensals while allowing for rapid development of an immune response to protect against the invader. Failure to achieve this has pathological consequences such as the development of inflammatory bowel diseases (Gastrointestinal tract) and Periodontitis (Oral mucosa). Consequently, specialized immune cell networks have developed to help mediate effective immunological control of these dynamic barrier environments.
My research programme focuses on understanding how the immune system is tailored to these unique barrier surfaces and how these networks evolve with age. Indeed, to mediate immune homeostasis at the barrier sites of GI tract and oral mucosa, conventional and unconventional immune cells are present which are conditioned by the microenvironment. My recent work has examined the development and differentiation of T cells at barrier sites, understanding how barrier-specific cues, in particular the cytokine TGFβ, eeducates T cells about their environment and drives them to adopt certain phenotypic and functional characteristics.
In my ongoing work I am further exploring the immune cell networks present at barrier sites, with a particular focus on the oral mucosa. Indeed, in a collaborative study, myself and others, have highlighted the key role of immune dysfunction in the development of Periodontitis, emphasizing the strict controls placed on immune cell functioning at the oral barrier. However, a clear picture of the immune homeostatic mechanisms at play at the oral barrier is yet to elucidated.
To address this I am undertaking parallel studies in both human and mouse that will allow for an in-depth investigation of this often overlooked mucosal site. Having been awarded a BBSRC David Phillips Fellowship, I aim to mechanistically understand the signals that are required to establish the immunological network present at the oral barrier and delineate how this network changes with age. This is an important question as advancing age is associated with loss of immune homeostasis at this unique barrier site. Collectively, this work will outline how alterations in the oral immuno-surveillance network contribute to immune dys-regulation and pathological inflammation in the oral cavity. In addition I am also exploring the influence of immune cell functioning at the oral barrier on immunity at distal sites, in particular the gastrointestinal tract, and identifying the meditators of this cross-talk.
Collectively, understanding the mechanisms behind immune specialization at barrier sites will not only allow for a better understanding of barrier immunity in human health and disease, but could also lead to the identification of targets for the rational development of novel therapeutics.
Moutsopoulos NM, Konkel J, Sarmadi M, Eskan MA, Wild T, Dutzan N, Abusleme L, Zenobia C, Hosur KB, Abe T, Uzel G, Chen W, Chavakis T, Holland SM, Hajishengallis G. 2014 Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.Sci Transl Med. Mar 26;6(229):229ra40. doi:10.1126/scitranslmed.3007696.
Kasagi S, Zhang P, Che L, Abbatiello B, Maruyama T, Nakatsukasa H, Zanvit P, Jin W, Konkel JE, Chen W. 2014 In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response.Sci Transl Med. Jun 18;6(241):241ra78. doi: 10.1126/scitranslmed.3008895.
Konkel JE, Jin W, Abbatiello B, Grainger JR, Chen W. 2014 Thymocyte apoptosis drives the intrathymic generation of regulatory T cells.Proc Natl Acad Sci U S A. Jan 28;111(4):E465-73. doi:10.1073/pnas.1320319111. Epub 2014 Jan 13.
Konkel JE, Chen W. 2011 Balancing acts: the role of TGF-β in the mucosal immune system. Trends Mol Med. Nov;17(11):668-76. doi:10.1016/j.molmed.2011.07.002. Epub 2011 Sep 2. Review.
Konkel JE, Maruyama T, Carpenter AC, Xiong Y, Zamarron BF, Hall BE, Kulkarni AB, Zhang P, Bosselut R, Chen W. 2011 Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat Immunol. Apr;12(4):312-9. doi: 10.1038/ni.1997. Epub 2011 Feb 6.