Dataset Information

SjHSP60 induces CD4+ CD25+ Foxp3+ Tregs via TLR4-Mal-drived production of TGF-? in macrophages.

ABSTRACT: CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a pivotal role in limiting immunopathological damage to host organs after schistosome infection. Transforming growth factor-? (TGF-?) is an essential factor for the periphery conversion of CD4+ CD25- T cells into CD4+ CD25+ Foxp3+ Tregs by inducing the key transcription factor Foxp3. Antigen presenting cells (APCs), which highly express TGF-?, are involved in parasite antigen-induced Treg conversion in peripheral. However, the mechanisms underlying high TGF-? induction in APCs by parasite antigens remain to be clarified during schistosome infection. Here, we demonstrated that Schistosoma japonicum stress protein, heat shock protein 60 (SjHSP60), promoted TGF-? production in macrophages (M?). Furthermore, we showed that activation of TLR4-Mal (MyD88 adaptor-like protein) signaling by SjHSP60 is necessary for induction of TGF-? expression in M?, which subsequently promoted Treg induction. Our results not only demonstrate a novel mechanism of TGF-? production in M? for inducing Tregs in mice with schistosomiasis, but also allude to the possibility of targeting parasite stress protein for potential therapeutics.

SUBMITTER: Zhou S

PROVIDER: S-EPMC6197892 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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SjHSP60 induces CD4+ CD25+ Foxp3+ Tregs via TLR4-Mal-drived production of TGF-β in macrophages.

Zhou Sha S Qi Qianqian Q Wang Xiaofan X Zhang Lina L Xu Lei L Dong Liyang L Zhu Jifeng J Li Yalin Y Wang Xuefeng X Xu Zhipeng Z Liu Feng F Hu Wei W Zhou Liang L Chen Xiaojun X Su Chuan C

Immunology and cell biology 20180521 9

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a pivotal role in limiting immunopathological damage to host organs after schistosome infection. Transforming growth factor-β (TGF-β) is an essential factor for the periphery conversion of CD4+ CD25- T cells into CD4+ CD25+ Foxp3+ Tregs by inducing the key transcription factor Foxp3. Antigen presenting cells (APCs), which highly express TGF-β, are involved in ...[more]

PMID: 29697865

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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

SjHSP60 induces CD4+ CD25+ Foxp3+ Tregs via TLR4-Mal-drived production of TGF-? in macrophages.

Publications

SjHSP60 induces CD4<sup>+</sup> CD25<sup>+</sup> Foxp3<sup>+</sup> Tregs via TLR4-Mal-drived production of TGF-β in macrophages.

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