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T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-beta/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). We identify the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) as a key negative regulator of human and mouse Th17 differentiation. PPAR gamma activation in CD4(+) T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPAR gamma involved inhibition of TGF-beta/IL-6-induced expression of ROR gamma t in T cells. Pharmacologic activation of PPAR gamma prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the ROR gamma t promoter in T cells, thus interfering with ROR gamma t transcription. Both T cell-specific PPAR gamma knockout and endogenous ligand activation revealed the physiological role of PPAR gamma for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4(+) T cells from healthy controls and MS patients were strongly susceptible to PPAR gamma-mediated suppression of Th17 differentiation. In summary, we report a PPAR gamma-mediated T cell-intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPAR gamma represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-beta/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). We identify the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) as a key negative regulator of human and mouse Th17 differentiation. PPAR gamma activation in CD4(+) T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPAR gamma involved inhibition of TGF-beta/IL-6-induced expression of ROR gamma t in T cells. Pharmacologic activation of PPAR gamma prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the ROR gamma t promoter in T cells, thus interfering with ROR gamma t transcription. Both T cell-specific PPAR gamma knockout and endogenous ligand activation revealed the physiological role of PPAR gamma for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4(+) T cells from healthy controls and MS patients were strongly susceptible to PPAR gamma-mediated suppression of Th17 differentiation. In summary, we report a PPAR gamma-mediated T cell-intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPAR gamma represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

Background: Infarct size is an important predictor of cardiac risk after acute myocardial infarction. The established modality for its assessment is Tc99m-Sestamibi Single-photon emission computed tomography (SPECT). In recent years, data are emerging demonstrating that scar size as assessed by late gadolinium enhancement in cardiovascular magnetic resonance imaging (CMR) as well as the presence of microvascular obstruction (MO) may also provide prognostic information, however, so far no direct comparisons of both modalities have been reported., Methods: We retrospectively analysed patients (n = 281) with acute ST-elevation myocardial infarction and primary angioplasty who underwent Tc99m-Sestamibi-SPECT and CMR on a 1.5 T scanner at a median of 4.3 (IQR: 3.7-5.1) and 4.9 (IQR: 4.1-5.9) days after the acute event, respectively. The primary endpoint of the study was a composite of all-cause mortality, recurrent myocardial infarction and congestive heart failure requiring hospitalization., Results: During a median follow-up of 3.0 (IQR: 2.0-4.5) years, 24 events occurred. The best predictor was MO (P < 0.0001), followed by infarct size by CMR (P = 0.0043) and infarct size by SPECT (P = 0.012) (all P-values corrected for clinical risk). In a multivariate model including clinical and periprocedural parameters, MO remained the only significant predictor in addition to clinical risk., Conclusions: The extent of MO as determined by CMR has an excellent prognostic value in predicting cardiac events following acute myocardial infarction and may be used as an alternative to infarct size assessment by Tc99m-Sestamibi-SPECT.