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Compensatory roles of CD8+ T cells and plasmacytoid dendritic cells in gut immune regulation for reduced function of CD4+ Tregs.

ABSTRACT: CD4+ Tregs need to migrate from the mucosal periphery into the draining lymph node via CCR7 to exert their suppressive effects. In this study, we investigated whether CCR7 deficiency resulted in failure of immune suppression in 2% dextran sulfate sodium-induced colitis. Unexpectedly, intestinal inflammation was not exacerbated in the absence of CCR7. Expression of IL-10, a representative suppressive cytokine, was enhanced in CCR7KO CD8+ T cells. Colon CCR7KO CD8+ T cells reduced the activation of CD4+ T cells. Depletion of CD8+ T cells using anti-CD8 antibody exacerbated colitis in CCR7KO mice. Plasmacytoid dendritic cell numbers were also slightly increased during intestinal inflammation in the absence of CCR7, and the depletion of those cells exacerbated DSS-induced colitis in CCR7KO mice. These results suggest that CD8+ T cells and plasmacytoid dendritic cells have compensatory roles in immune regulation in the gut for impaired function of CD4+ Tregs.

SUBMITTER: Kim YI

PROVIDER: S-EPMC4905450 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Compensatory roles of CD8+ T cells and plasmacytoid dendritic cells in gut immune regulation for reduced function of CD4+ Tregs.

Kim Young-In YI Lee Bo-Ra BR Cheon Jae-Hee JH Kwon Bo-Eun BE Kweon Mi-Na MN Ko Hyun-Jeong HJ Chang Sun-Young SY

Oncotarget 20160301 10

CD4+ Tregs need to migrate from the mucosal periphery into the draining lymph node via CCR7 to exert their suppressive effects. In this study, we investigated whether CCR7 deficiency resulted in failure of immune suppression in 2% dextran sulfate sodium-induced colitis. Unexpectedly, intestinal inflammation was not exacerbated in the absence of CCR7. Expression of IL-10, a representative suppressive cytokine, was enhanced in CCR7KO CD8+ T cells. Colon CCR7KO CD8+ T cells reduced the activation o ...[more]

PMID: 26908454

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Project description:BackgroundRegulatory T cells (Tregs) were shown to be central in maintaining immunological homeostasis and preventing the development of autoimmune diseases. Several subsets of Tregs have been identified to date; however, the dynamics of the interactions between these subsets, and their implications on their regulatory functions are yet to be elucidated.Methodology/principal findingsWe employed a combination of mathematical modeling and frequent in vivo measurements of several T cell subsets. Healthy BALB/c mice received a single injection of either hCDR1--a tolerogenic peptide previously shown to induce Tregs, a control peptide or vehicle alone, and were monitored for 16 days. During this period, splenocytes from the treated mice were analyzed for the levels of CD4, CD25, CD8, CD28 and Foxp3. The collected data were then fitted to mathematical models, in order to test competing hypotheses regarding the interactions between the followed T cell subsets. In all 3 treatment groups, a significant, lasting, non-random perturbation of the immune system could be observed. Our analysis predicted the emergence of functional CD4 Tregs based on inverse oscillations of the latter and CD4(+)CD25(-) cells. Furthermore, CD4 Tregs seemed to require a sufficiently high level of CD8 Tregs in order to become functional, while conversion was unlikely to be their major source. Our results indicated in addition that Foxp3 is not a sufficient marker for regulatory activity.Conclusions/significanceIn this work, we unraveled the dynamics of the interplay between CD4, CD8 Tregs and effector T cells, using, for the first time, a mathematical-mechanistic perspective in the analysis of Treg kinetics. Furthermore, the results obtained from this interdisciplinary approach supported the notion that CD4 Tregs need to interact with CD8 Tregs in order to become functional. Finally, we generated predictions regarding the time-dependent function of Tregs, which can be further tested empirically in future work.

Dataset Information

Compensatory roles of CD8+ T cells and plasmacytoid dendritic cells in gut immune regulation for reduced function of CD4+ Tregs.

Publications

Compensatory roles of CD8+ T cells and plasmacytoid dendritic cells in gut immune regulation for reduced function of CD4+ Tregs.

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