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Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance.

ABSTRACT: Dendritic cells (DCs) have been shown to play a major role in oral tolerance, and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive regulatory T cells. In this study, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-myelin oligodendrocyte glycoprotein (MOG) carrying the MOG(35-55) epitope was orally administered into either T cell-sufficient or -deficient mice, only the T cell-sufficient hosts yielded CD8?(+) and CD8?(-) LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs upregulated programmed cell death ligand 1 during the initial interaction with MOG-specific T cells and used this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental autoimmune encephalomyelitis induced with CNS homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity.

SUBMITTER: Cascio JA

PROVIDER: S-EPMC3679289 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance.

Cascio Jason A JA Haymaker Cara L CL Divekar Rohit D RD Zaghouani Sarah S Khairallah Marie-Therese MT Wan Xiaoxiao X Rowland Linda M LM Dhakal Mermagya M Chen Weirong W Zaghouani Habib H

Journal of immunology (Baltimore, Md. : 1950) 20130517 12

Dendritic cells (DCs) have been shown to play a major role in oral tolerance, and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive regulatory T cells. In this study, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-myelin oligodendrocyte glycoprotein (MOG) carryin ...[more]

PMID: 23686493

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Project description:BackgroundSalmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9-20.6 million infections and ~ 130,000-223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5-7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (TRM) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces TRM in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+TRM subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments.MethodsTerminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+TRM immune responses were determined using either S. Typhi-infected or non-infected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers).ResultsAlthough the frequencies of LPMC CD103+ CD4+TRM were significant decreased, both CD103+ and CD103- CD4+TRM subsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+TRM (IFNγ and IL-17A) and CD103- CD4+TRM (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+TRM subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103- CD4+TRM (increase) following immunization. Finally, we observed that IEL CD103- CD4+TRM, but not CD103+ CD4+TRM, produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization.ConclusionsOral Ty21a-immunization elicits distinct compartment specific immune responses in CD4+TRM (CD103+ and CD103-) subsets. This study provides novel insights in the generation of local vaccine-specific responses. Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304, Registered 29 May 2019-Retrospectively registered, http://www.ClinicalTrials.gov/NCT03970304).

Dataset Information

Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance.

Publications

Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance.

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