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. 2013 Apr 9;110(15):6193-8.
doi: 10.1073/pnas.1210644110. Epub 2013 Mar 25.

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Giuseppe Matarese  1 , Claudio Procaccini, Ciro Menale, Jae Geun Kim, Jung Dae Kim, Sabrina Diano, Nadia Diano, Veronica De Rosa, Marcelo O Dietrich, Tamas L Horvath
Affiliations

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Giuseppe Matarese et al. Proc Natl Acad Sci U S A. .

Abstract

Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4(+) T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3(+)) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Thymic phenotype and effects of selective ablation of Sirt1 in Agrp neurons in the generation of thymic-derived naturally occurring Treg cells. (A) Morphology of thymus from WT and AgRP-Sirt1 KO mice. (B) Cell numbers of thymocytes in WT (black columns) and AgRP-Sirt1 KO (gray columns) mice. Data are shown as mean ± SD (n = 5 mice/group). (C) CD4 and CD8 expression in the thymus from WT and AgRP-Sirt1 KO mice. One representative out of three independent experiments. (D) Ex vivo analysis of the percentage of Treg, PCNA, and S6 expression in Treg cells from the thymus of WT and AgRP-Sirt1 KO mice. (n = 3 mice/group, one representative out of three independent experiments). (E) Percentage of BrdU-positive cells upon anti-CD3/CD28 stimulation in thymic-derived Treg cells from WT (black column) and AgRP-Sirt1 KO (gray column) mice. The data are shown as mean ± SD (n = 5 mice/group; *P < 0.001). (F) Immunoblot for P-S6 and its relative densitometric quantification in purified thymic-derived Treg cells from WT (black column) and AgRP-Sirt1 KO (gray column) mice. One representative out of three independent experiments.
Fig. 2.
Fig. 2.
Effect of selective Sirt1 ablation in AgRP neurons on the control of CD4+ T-cell functions. (A) Proliferative response of lymph node-derived T cells from WT (black columns) and AgRP-Sirt1 KO (gray columns) mice, stimulated or not with anti-CD3 for 48 h. Data are shown as mean ± SD (n = 5 mice/group; *P < 0.0001, **P < 0.05). (B) IL-2, IL-6, IL-17, IFN-γ, TNF-a, IL-4, IL-5, and IL-10 production in cell supernatant from lymph node-derived T cells from WT (black columns) and AgRP-Sirt1 KO (gray columns) mice. The data are shown as mean ± SD (n = 5 mice/group; *P < 0.001, **P < 0.05; NS, not significant). (C) Activation markers (CD25, CD54, and CD49d) expression gated on CD4+ T cells from WT (black histogram) and AgRP-Sirt1 KO (gray histogram) mice, stimulated with anti-CD3 after 36 h of culture. For each molecule the fold induction upon anti-CD3 stimulation is shown. Representative of five independent experiments. (D) Immunoblot for P-ERK1/2, ERK1/2, P-S6, S6, p27Kip1, and tubulin on lymph node-derived T cells from WT and AgRP- Sirt1 KO mice, stimulated or not with anti-CD3 for 1 h. The graphs show the relative densitometric protein quantification of P-ERK 1/2, P-S6, and p27Kip1 specifically of the gels shown in Fig. 1D from WT (black columns) and AgRP-Sirt1 KO (gray columns) mice. One representative out of three independent experiments.
Fig. 3.
Fig. 3.
Effect of selective Sirt1 ablation in AgRP neurons in the control of Treg cell functions. (A) Flow cytometry ex vivo analysis of PCNA (Left) and PS6 (Right) in Treg cells from the lymph nodes of WT and AgRP-Sirt1 KO mice. (n = 3 mice/group, representative of three independent experiments). (B) Proliferation, IL-2, IL-17, and IFN-γ production by Teff cells in coculture with Treg cells from WT and AgRP-Sirt1 KO mice treated or not in vivo with propranolol and SR59230A, upon anti-CD3/CD28 stimulation. The data are shown as mean ± SD (n = 5 mice/group; *P < 0.0001, **P < 0.05). (C) IL-10, TGF-β, and IL-4 production in purified Treg cells from WT (black columns) and AgRP-Sirt1 KO (gray columns) mice treated or not in vivo with propranolol and SR59230A, upon anti-CD3/CD28 stimulation. (n = 5 mice/group; *P < 0.001; NS, not significant).
Fig. 4.
Fig. 4.
Effect of selective Sirt1 ablation in AgRP neurons on DTH responses and EAE susceptibility. (A) Seven days after sensitization with MOG35–55 in CFA, mice were challenged by injection of MOG35–55 into the footpad and then assessed for DTH responses (footpad-swelling assay) 0, 12, 24, 48, 72, and 96 h later. Data are showing the means of percentage of increase ± SD of footpad-swelling responses (n = 6 mice/group; *P < 0.05). (B) EAE mean clinical course and severity in AgRP-Sirt1 KO mice and WT control littermates. Mutant animals had a more severe clinical course than WT animals. One representative experiment (n = 5 mice/group; *P < 0.05). (C) Inflammatory lesions in brain parenchyma from WT (Left) and AgRP-Sirt1 KO mice (Right) stained with hematoxylin and eosin. (Magnification, ×200.) (D) Summary of the inflammatory lesions in brain of WT and AgRP-Sirt1 KO mice. Results are expressed as the mean histological score ± SD (n = 4–10 sections/mouse) (n = 5 mice/group; *P < 0.05). (E) MOG35–55 peptide-specific proliferation and IFN-γ production (F) of lymph node cells from WT and AgRP-Sirt1 KO mice 20 d (peak of disease) after immunization. Data are shown as mean ± SD (n = 5 mice/group; *P < 0.001).
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