title: Bistability analyses of CD4+ T follicular helper and regulatory cells during Helicobacter pylori infection.
abstract: T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori.
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leber
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: Vida
authors.initials: V
authors.lastname: Abedi
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Viladomiu
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoops
authors.affiliation: Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Department of Mathematics, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Stanca
authors.initials: S
authors.lastname: Ciupe
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Caughman
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
authors.forename: Tricity
authors.initials: T
authors.lastname: Andrew
authors.affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA; Center for Modeling Immunity to Enteric Pathogens, Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA. Electronic address: jbassaga@vt.edu.
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003198:Computer Simulation; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012097:Repressor Proteins / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D013269:Stochastic Processes; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; D047488:Retinoid X Receptors; C490797:Tgif1 protein, mouse
keywords: Bistability analysis; CD4+ T cell differentiation; Computational modeling; H. pylori; T follicular helper cell