The vast gut-associated immune system, which accounts for most of the lymphocytes and antibodies in the body, must inhibit penetration and spreading of pathogens while controlling excessive or unnecessary immune responses that could jeopardize the integrity of the mucosal epithelial barrier. Although CD4 helper T cells are crucial for the generation of efficient immune responses, uncontrolled CD4 helper T cells can pose a threat to an organism. The CD4 fate is initially induced in thymocytes and continuously maintained in mature T cells by the zinc finger transcription factor, ThPOK, while CD8 cytotoxic T cell fate depends on the transcription factor of Runt family, Runx3. We recently found a gut specific and highly plastic process that drives the downregulation of ThPOK in CD4 T cells upon migration to the intestinal epithelium. The loss of ThPOK by mature CD4 T cells is accompanied by suppression of T cell helper function, particularly the Th17 phenotype, and upregulation of Runx3 and cytotoxic-related molecules. It is of utmost interest to defie factors that regulate the stability of helper T cells and functional consequences of modulation of these transcription factors in mature CD4 helper T cells. We hypothesize that during migration from the periphery to the intestinal compartment, activated CD4 T cells are exposed to several environmental factors that may orchestrate this process. This study will use novel genetically modified mouse strains and germ-free animals to investigate the role of intestinal-derived factors including TGF-?, retinoic acid and commensal bacteria, in the modulation of CD4 helper T function. Additionally, bioinformatics associated with epigenetics techniques will be used to define upstream mechanisms that drive ThPOK and Runx3 modulation as to identify downstream targets involved in helper T cell function. Finally, the functional consequences of this unpredicted plasticity of helper T cells will be studied using models of infection and inflammatory bowel diseases (IBD). In vivo experiments will determine how the modulation of ThPOK and Runx3 expression in the intestine influences the capacity of CD4 T cells to cause or control inflammation. While the concomitant loss of ThPOK and acquisition of Runx3 may be beneficial to avoid excessive inflammation and tissue destruction, it may be detrimental when specific. The cytokines are required for immune protection. The studies proposed here will directly address functional implications of the peripheral plasticity of CD4 T cells, induced by intestinal milieu, in the IBD pathogenesis and in the control of intestinal infections. This proposal uses exclusively novel concepts, dissecting a physiological pathway that shifts helper T cells towards cytotoxic T cells in the intestine, to address the biology behin CD4 T cells helper differentiation and function. Therefore, by the knowledge gained from this study will expand our understanding of the development and modulation of the adaptive immunity, providing valuable information regarding host-microbial interactions and vaccination strategies.
The proposed research has significant relevance to public health because it directly addresses possible cellular and molecular mechanisms involved in the development of human inflammatory bowel diseases. By pursuing an understanding of the main components and interactions of the intestine/microbes/immune system network, this proposal may provide novel strategies for the development of mucosal vaccines and new therapeutic avenues for the treatment of inflammatory bowel diseases, celiac disease and food allergies.
|Faria, Ana M C; Reis, Bernardo S; Mucida, Daniel (2017) Tissue adaptation: Implications for gut immunity and tolerance. J Exp Med 214:1211-1226|
|Hoytema van Konijnenburg, David P; Reis, Bernardo S; Pedicord, Virginia A et al. (2017) Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection. Cell 171:783-794.e13|
|Sujino, Tomohisa; London, Mariya; Hoytema van Konijnenburg, David P et al. (2016) Tissue adaptation of regulatory and intraepithelial CD4? T cells controls gut inflammation. Science 352:1581-6|
|Rogoz, Aneta; Reis, Bernardo S; Karssemeijer, Roos A et al. (2015) A 3-D enteroid-based model to study T-cell and epithelial cell interaction. J Immunol Methods 421:89-95|
|Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H et al. (2015) Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol 194:5253-60|
|Reis, Bernardo S; Hoytema van Konijnenburg, David P; Grivennikov, Sergei I et al. (2014) Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. Immunity 41:244-56|
|Esterházy, Daria; Mucida, Daniel (2014) Serum amyloid A proteins take retinol for a ride. Trends Immunol 35:505-6|
|Reis, Bernardo Sgarbi; Rogoz, Aneta; Costa-Pinto, Frederico Azevedo et al. (2013) Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4? T cell immunity. Nat Immunol 14:271-80|
|Mucida, Daniel; Husain, Mohammad Mushtaq; Muroi, Sawako et al. (2013) Transcriptional reprogramming of mature CD4? helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat Immunol 14:281-9|