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Non-classical MHC I-E negatively regulates macrophage activation and Th17 cell development in NOD mice.

Yang C, Guo N, Liu J, Yang J, Zhu K, Xiao H, Leng Q - Sci Rep (2015)

Bottom Line: The reduction in Th17 cells was associated with both attenuated IL-6 production and decreased activation of macrophages.In contrast to classical MHC II molecule, this non-classical MHC II molecule negatively regulates the inflammatory responses of macrophages.Altogether, our study reveals a novel regulatory role of I-E molecules in modulating inflammatory immune responses.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China.

ABSTRACT
Transgenic expression of I-E molecules prevents diabetes in NOD mice. So far, the precise role of these non-classical MHC II molecules remains elusive. Here, we showed that transgenic expression of I-E(k) alpha 16 molecule in NOD mice selectively reduced Th17 cells in the thymus and pancreatic draining lymph nodes. The reduction in Th17 cells was associated with both attenuated IL-6 production and decreased activation of macrophages. Mechanistically, transgenic expression of the I-E molecule diminished expression of intracellular classical MHC II molecule and led to impaired TLR4-mediated signaling. In contrast to classical MHC II molecule, this non-classical MHC II molecule negatively regulates the inflammatory responses of macrophages. Altogether, our study reveals a novel regulatory role of I-E molecules in modulating inflammatory immune responses.

No MeSH data available.


Related in: MedlinePlus

Effects of transgenic I-E expression on the development of CD4+ T cell subsets.(A-C) Percentages of CD25+Foxp3+ Treg (A), IFN-γ-producing Th1 (B) and IL-17A-producing Th17 (C) cell populations in CD4+CD8- single positive (CD4 SP) cells from the spleens and thymi of Ea16-transgenic (EA16) and wild-type (WT) NOD mice. (D) Absolute numbers of Th1 and Th17 populations in the thymi from EA16 and WT mice were shown. (E-F) Percentages of the Th subsets (E) and CD44+CCR6+ population (F) in CD4+ T cells in PPs and PDLNs from EA16 and WT NOD mice were shown. Data (mean ± SEM) are representative of two (E) or three (A-D,F) independent experiments with similar results (n = 6 per group). *P < 0.05.
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f1: Effects of transgenic I-E expression on the development of CD4+ T cell subsets.(A-C) Percentages of CD25+Foxp3+ Treg (A), IFN-γ-producing Th1 (B) and IL-17A-producing Th17 (C) cell populations in CD4+CD8- single positive (CD4 SP) cells from the spleens and thymi of Ea16-transgenic (EA16) and wild-type (WT) NOD mice. (D) Absolute numbers of Th1 and Th17 populations in the thymi from EA16 and WT mice were shown. (E-F) Percentages of the Th subsets (E) and CD44+CCR6+ population (F) in CD4+ T cells in PPs and PDLNs from EA16 and WT NOD mice were shown. Data (mean ± SEM) are representative of two (E) or three (A-D,F) independent experiments with similar results (n = 6 per group). *P < 0.05.

Mentions: Given the contradictory findings regarding the role of transgenic I-E in the negative selection of self-reactive CD4+ T cells, we wondered whether the I-E molecule affects the development of CD4+ T-cell subsets in I-E transgenic mice. To test this possibility, we examined Th1, Th17 and regulatory T (Treg) subsets in wild-type (WT) NOD mice and in EA16 mice, which transgenically express the I-Ek alpha 16 gene6. The percentages of Treg cells in the thymus and spleen of EA16 mice did not differ significantly from those of WT NOD mice (Fig. 1A). Similarly, the percentages of IFN-γ-producing (Th1) and IL-17A-producing (Th17) CD4+ T cells in the spleen of EA16 mice were not significantly different from those of WT NOD mice (Fig. 1B-C); whereas in the thymus, Th1 and Th17 cells of EA16 mice dropped proximately 68% and 56%, respectively (Fig. 1B-D). We further examined the proliferation rates of thymocytes with intracellular staining of Ki-67, a proliferation marker. Although both Th1 an Th17 cells in thymus similarly proliferated 4–5 times higher than total CD4 single-positive thymocytes, the proliferation rates of these two subsets in EA16 mice were not significantly different from WT NOD mice (Fig. S1). Thus, the decease of thymic Th1 and Th17 cells of EA16 mice unlikely results from a decrease of proliferation.


Non-classical MHC I-E negatively regulates macrophage activation and Th17 cell development in NOD mice.

Yang C, Guo N, Liu J, Yang J, Zhu K, Xiao H, Leng Q - Sci Rep (2015)

Effects of transgenic I-E expression on the development of CD4+ T cell subsets.(A-C) Percentages of CD25+Foxp3+ Treg (A), IFN-γ-producing Th1 (B) and IL-17A-producing Th17 (C) cell populations in CD4+CD8- single positive (CD4 SP) cells from the spleens and thymi of Ea16-transgenic (EA16) and wild-type (WT) NOD mice. (D) Absolute numbers of Th1 and Th17 populations in the thymi from EA16 and WT mice were shown. (E-F) Percentages of the Th subsets (E) and CD44+CCR6+ population (F) in CD4+ T cells in PPs and PDLNs from EA16 and WT NOD mice were shown. Data (mean ± SEM) are representative of two (E) or three (A-D,F) independent experiments with similar results (n = 6 per group). *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528198&req=5

f1: Effects of transgenic I-E expression on the development of CD4+ T cell subsets.(A-C) Percentages of CD25+Foxp3+ Treg (A), IFN-γ-producing Th1 (B) and IL-17A-producing Th17 (C) cell populations in CD4+CD8- single positive (CD4 SP) cells from the spleens and thymi of Ea16-transgenic (EA16) and wild-type (WT) NOD mice. (D) Absolute numbers of Th1 and Th17 populations in the thymi from EA16 and WT mice were shown. (E-F) Percentages of the Th subsets (E) and CD44+CCR6+ population (F) in CD4+ T cells in PPs and PDLNs from EA16 and WT NOD mice were shown. Data (mean ± SEM) are representative of two (E) or three (A-D,F) independent experiments with similar results (n = 6 per group). *P < 0.05.
Mentions: Given the contradictory findings regarding the role of transgenic I-E in the negative selection of self-reactive CD4+ T cells, we wondered whether the I-E molecule affects the development of CD4+ T-cell subsets in I-E transgenic mice. To test this possibility, we examined Th1, Th17 and regulatory T (Treg) subsets in wild-type (WT) NOD mice and in EA16 mice, which transgenically express the I-Ek alpha 16 gene6. The percentages of Treg cells in the thymus and spleen of EA16 mice did not differ significantly from those of WT NOD mice (Fig. 1A). Similarly, the percentages of IFN-γ-producing (Th1) and IL-17A-producing (Th17) CD4+ T cells in the spleen of EA16 mice were not significantly different from those of WT NOD mice (Fig. 1B-C); whereas in the thymus, Th1 and Th17 cells of EA16 mice dropped proximately 68% and 56%, respectively (Fig. 1B-D). We further examined the proliferation rates of thymocytes with intracellular staining of Ki-67, a proliferation marker. Although both Th1 an Th17 cells in thymus similarly proliferated 4–5 times higher than total CD4 single-positive thymocytes, the proliferation rates of these two subsets in EA16 mice were not significantly different from WT NOD mice (Fig. S1). Thus, the decease of thymic Th1 and Th17 cells of EA16 mice unlikely results from a decrease of proliferation.

Bottom Line: The reduction in Th17 cells was associated with both attenuated IL-6 production and decreased activation of macrophages.In contrast to classical MHC II molecule, this non-classical MHC II molecule negatively regulates the inflammatory responses of macrophages.Altogether, our study reveals a novel regulatory role of I-E molecules in modulating inflammatory immune responses.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China.

ABSTRACT
Transgenic expression of I-E molecules prevents diabetes in NOD mice. So far, the precise role of these non-classical MHC II molecules remains elusive. Here, we showed that transgenic expression of I-E(k) alpha 16 molecule in NOD mice selectively reduced Th17 cells in the thymus and pancreatic draining lymph nodes. The reduction in Th17 cells was associated with both attenuated IL-6 production and decreased activation of macrophages. Mechanistically, transgenic expression of the I-E molecule diminished expression of intracellular classical MHC II molecule and led to impaired TLR4-mediated signaling. In contrast to classical MHC II molecule, this non-classical MHC II molecule negatively regulates the inflammatory responses of macrophages. Altogether, our study reveals a novel regulatory role of I-E molecules in modulating inflammatory immune responses.

No MeSH data available.


Related in: MedlinePlus