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CD4+ T helper (TH) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How TH differentiation is regulated by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on TH cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired TH1 differentiation without obviously affecting TH2 and TH17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted TH1 and TH17 differentiation in vitro and in vivo , leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of TH17 differentiation of DGKα and ζ double-deficient CD4+ T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is one of the most common neurological disorders in young adults. The etiology of MS is not known but it is widely accepted that it is autoimmune in nature. Disease onset is believed to be initiated by the activation of CD4+ T cells that target autoantigens of the central nervous system (CNS) and their infiltration into the CNS, followed by the expansion of local and infiltrated peripheral effector myeloid cells that create an inflammatory milieu within the CNS, which ultimately lead to tissue damage and demyelination. Clinical studies have shown that progression of MS correlates with the abnormal expression of certain cytokines. The use of experimental autoimmune encephalomyelitis (EAE) model further delineates the role of these cytokines in neuroinflammation and the therapeutic potential of manipulating their biological activity in vivo. In this review, we will first present an overview on cytokines that may contribute to the pathogenesis of MS or EAE, and provide successful examples and roadblock of translating data obtained from EAE to MS. We will then focus in depth on recent findings that demonstrate the pathological role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in MS and EAE, and briefly discuss the potential of targeting effector myeloid cells as a treatment strategy for MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated disease that predominantly impacts the central nervous system (CNS). Animal models have been used to elucidate the underpinnings of MS pathology. One of the most well-studied models of MS is experimental autoimmune encephalomyelitis (EAE). This model was utilized to demonstrate that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical and non-redundant role in mediating EAE pathology, making it an ideal therapeutic target. In this review, we will first explore the role that GM-CSF plays in maintaining homeostasis. This is important to consider, because any therapeutics that target GM-CSF could potentially alter these regulatory processes. We will then focus on current findings related to the function of GM-CSF signaling in EAE pathology, including the cell types that produce and respond to GM-CSF and the role of GM-CSF in both acute and chronic EAE. We will then assess the role of GM-CSF in alternative models of MS and comment on how this informs the understanding of GM-CSF signaling in the various aspects of MS immunopathology. Finally, we will examine what is currently known about GM-CSF signaling in MS, and how this has promoted clinical trials that directly target GM-CSF.

Mucosal-associated invariant T (MAIT) cells participate in both protective immunity and pathogenesis of diseases. Most murine MAIT cells express an invariant TCRVα19-Jα33 (iVα19) TCR, which triggers signals crucial for their development. However, signal pathways downstream of the iVα19TCR and their regulation in MAIT cells are unknown. Diacylglycerol (DAG) is a critical second messenger that relays the TCR signal to multiple downstream signaling cascades. DAG is terminated by DAG kinase (DGK)-mediated phosphorylation and conversion to phosphatidic acid. We have demonstrated here that downregulation of DAG caused by enhanced DGK activity impairs late-stage MAIT cell maturation in both thymus and spleen. Moreover, deficiency of DGKζ but not DGKα by itself causes modest decreases in MAIT cells, and deficiency of both DGKα and ζ results in severe reductions of MAIT cells in an autonomous manner. Our studies have revealed that DAG signaling is not only critical but also must be tightly regulated by DGKs for MAIT cell development and that both DGKα and, more prominently, DGKζ contribute to the overall DGK activity for MAIT cell development., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

CD4 + T helper (T H ) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How T H differentiation is regulated by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on T H cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired T H 1 differentiation without obviously affecting T H 2 and T H 17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted T H 1 and T H 17 differentiation in vitro and in vivo , leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of T H 17 differentiation of DGKα and ζ double-deficient CD4 + T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling., (Copyright © 2020 Yang, Wang, Xie, Li, Wang, Wan and Zhong.)