A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T cell subset in exhausted CD8+ T cells in chronic infection1–3, but it remains unclear whether CD4+ T cell subsets with similar features exist in chronic inflammatory conditions. Among helper T cells, TH17 cells play prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4–7, although the regulation of plasticity is poorly understood. Here we demonstrate that TH17 cells in autoimmune disease are functionally and metabolically heterogeneous and contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports the transdifferentiation into TH1 cells. These two TH17 cell subsets are defined by selective expression of transcription factors TCF-1 and T-bet, and discrete CD27 expression levels. Moreover, we identify mTORC1 signaling as a central regulator to orchestrate TH17 cell fates by coordinating metabolic and transcriptional programs. TH17 cells with disrupted mTORC1 or anabolic metabolism fail to induce autoimmune neuroinflammation or develop into TH1-like cells, but instead upregulate TCF-1 expression and activity and acquire stemness-associated features. Single cell RNA-sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon mTORC1 deletion or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of helper T cell plasticity.

Adaptive immune response has been implicated in inflammation and fibrosis as a result of exposure to mineralocorticoids and a high-salt diet. We hypothesized that in mineralocorticoid-salt–induced hypertension, activation of the mineralocorticoid receptor alters the T-helper 17 lymphocyte (Th17)/regulatory T-lymphocyte/interleukin-17 (IL-17) pathway, contributing to cardiac and renal damage. We studied the inflammatory response and tissue damage in rats treated with deoxycorticosterone acetate and high-salt diet (DOCA–salt), with or without mineralocorticoid receptor inhibition by spironolactone. To determine whether Th17 differentiation in DOCA–salt rats is caused by hypertension per se, DOCA–salt rats received antihypertensive therapy. In addition, to evaluate the pathogenic role of IL-17 in hypertension and tissue damage, we studied the effect of IL-17 blockade with a specific antibody (anti–IL-17). We found activation of Th17 cells and downregulation of forkhead box P3 mRNA in peripheral tissues, heart, and kidneys of DOCA–salt–treated rats. Spironolactone treatment prevented Th17 cell activation and increased numbers of forkhead box P3–positive cells relative to DOCA–salt rats. Antihypertensive therapy did not ameliorate Th17 activation in rats. Treatment of DOCA–salt rats with anti–IL-17 significantly reduced arterial hypertension as well as expression of profibrotic and proinflammatory mediators and collagen deposits in the heart and kidney. We conclude that mineralocorticoid receptor activation alters the Th17/regulatory T-lymphocyte/IL-17 pathway in mineralocorticoid-dependent hypertension as part of an inflammatory mechanism contributing to fibrosis.

Dendritic cells (DCs) are responsible for priming T cells and for promoting their differentiation from naive T cells into appropriate effector cells. Emerging evidence suggests that neurotransmitters can modulate T cell-mediated immunity. However, the involvement of specific neurotransmitters or receptors remains poorly understood. In this study, we analyzed the role of dopamine in the regulation of DC function. We found that DCs express dopamine receptors as well as the machinery necessary to synthesize, store, and degrade dopamine. Notably, the expression of D5R decreased upon LPS-induced DC maturation. Deficiency of D5R on the surface of DCs impaired LPS-induced IL-23 and IL-12 production and consequently attenuated the activation and proliferation of Ag-specific CD4+ T cells. To determine the relevance of D5R expressed on DCs in vivo, we studied the role of this receptor in the modulation of a CD4+ T cell-driven autoimmunity model. Importantly, D5R-deficient DCs prophylactically transferred into wild-type recipients were able to reduce the severity of experimental autoimmune encephalomyelitis. Furthermore, mice transferred with D5R-deficient DCs displayed a significant reduction in the percentage of Th17 cells infiltrating the CNS without differences in the percentage of Th1 cells compared with animals transferred with wild-type DCs. Our findings demonstrate that by contributing to CD4+ T cell activation and differentiation to Th17 phenotype, D5R expressed on DCs is able to modulate the development of an autoimmune response in vivo.

Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8+ T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-b in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4+ T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8+ T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease.This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico Grants 1070352, 1070876, 1050265, 1050690 and 1050979; Fondo de Fomento al Desarrollo Científico y Tecnológico Grant D04I1075; INCO-CT-2006-032296; and Millennium Nucleus on Immunology and Immunotherapy (P04/030-F).A.A.H., P.A.G, and C.A.A. are fellows of Comisión Nacional de Investigación Científica y Tecnológica