ABSTRACT
De-regulated T-cell activation and functions are pivotal in the orchestration of immune-mediated tissue damage in IBD. We investigated the role of DNAM-1 (co-activating)/TIGIT (co-inhibitory)/ligand axis in the regulation of T-cell functions and its involvement in IBD pathogenesis. We show that DNAM-1 and TIGIT display a peculiar expression pattern on gut mucosa T-cell populations, in a microenvironment where their shared ligands (PVR and Nectin-2) are physiologically present. Moreover, DNAM-1 family receptor/ligand system is perturbed in IBD lesions, in a disease activity-dependent manner. The expression profile of CCR6 and CD103 mucosa addressins suggests that microenvironment-associated factors, rather than skewed recruitment of circulating T-cell populations, play a more relevant role in supporting the establishment of DNAM-1 and TIGIT expression pattern in mucosal T-cell populations, and may explain its alteration in IBD. Although both co-receptors mark functionally competent T cells, DNAM-1 and TIGIT segregate on T cells endowed with different proliferative potential. Moreover, their opposing role in regulating T-cell proliferation exquisitely depends on ligand availability. All together, our data propose a role for DNAM-1 and TIGIT in regulating mucosal T-cell activation and immune homeostasis, and highlight the involvement of an imbalance of this system in IBD.
Subject(s)
Antigens, Differentiation, T-Lymphocyte/metabolism , Colon/metabolism , Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/metabolism , Lymphocyte Activation , Receptors, Immunologic/metabolism , T-Lymphocytes/metabolism , Adolescent , Age Factors , Case-Control Studies , Cell Proliferation , Cellular Microenvironment , Child , Child, Preschool , Colon/immunology , Female , HT29 Cells , Humans , Immunity, Mucosal , Infant , Inflammatory Bowel Diseases/immunology , Intestinal Mucosa/immunology , Male , Nectins/metabolism , Receptors, Virus/metabolism , Signal Transduction , T-Lymphocytes/immunologyABSTRACT
Toxoneuron nigriceps (Viereck) (Hymenoptera, Braconidae) is an endophagous parasitoid of the tobacco budworm Heliothis virescens (F.) (Lepidoptera, Noctuidae). Parasitized H. virescens larvae are developmentally arrested and show a complex array of pathological symptoms ranging from the suppression of the immune response to an alteration of ecdysone biosynthesis and metabolism. Most of these pathological syndromes are induced by the polydnavirus associated with T. nigriceps (TnBV). An overview of our recent research work on this system is described herein. The mechanisms involved in the disruption of the host hormonal balance have been further investigated, allowing to better define the physiological model previously proposed. A functional genomic approach has been undertaken to identify TnBV genes expressed in the host and to assess their role in the major parasitoid-induced pathologies. Some TnBV genes cloned so far are novel and do not show any similarity with genes already available in genomic databases, while others code for proteins having conserved domains, such as aspartic proteases and tyrosine phosphatases. Sequencing of the entire TnBV genome is in progress and will considerably contribute to the understanding of the molecular bases of parasitoid-induced host alterations.
Subject(s)
Hymenoptera/physiology , Lepidoptera/physiology , Lepidoptera/parasitology , Amino Acid Sequence , Animals , Aspartic Acid Endopeptidases/biosynthesis , Aspartic Acid Endopeptidases/genetics , Endocrine Glands/physiology , Gene Expression , Genes, Viral , Genome, Viral , Host-Parasite Interactions , Hymenoptera/genetics , Hymenoptera/virology , Larva/growth & development , Larva/metabolism , Lepidoptera/genetics , Molecular Sequence Data , Polydnaviridae/enzymology , Polydnaviridae/genetics , Viral Structural Proteins/geneticsABSTRACT
Mucosal interleukin (IL)-17A-producing T cells contribute to protective antimicrobial responses and to epithelial barrier integrity; their role in celiac disease (CD) is debated. We analyzed the frequency and developmental dynamics of mucosal (intraepithelial lymphocytes (IEL)) and circulating (peripheral blood (PB)) IL-17A (T17) and/or interferon (IFN)-γ-producing (T1, T1/T17) T-cell populations in 86 pediatric controls and 116 age-matched CD patients upon phorbol myristate acetate/ionomycin or CD3/CD28 stimulation. T17 and T1/17 are physiologically present among IEL and PB populations, and their frequency is selectively and significantly reduced in CD IEL. The physiological age-dependent increase of Th17 IEL is also absent in CD, while IFN-γ-producing PB-T cells significantly accumulate with patient's age. Finally, the amplitude of IL-17A+ and IFN-γ+ T-cell pools are significantly correlated in different individuals; this relationship only applies to CD4+ T cells in controls, while it involves also the CD4- counterpart in CD patients. In conclusion, both size and dynamics of mucosa-associated and circulating IL-17A+ T-cell pools are finely regulated in human pediatric subjects, and severely disturbed in CD. The impaired IL-17A+ IEL-T pool may negatively impact on epithelial barrier efficiency, and contribute to CD mucosa damage; the disturbed dynamics of circulating IL-17A+ and IFN-γ+ T-cell pools may be involved in the extraintestinal autoimmune manifestations associated with CD.