Foxp3+ regulatory T (Treg) cells are the major gatekeepers of the immune system for the maintenance of self-tolerance and immune homeostasis. Treg cell development rests on the key activities of the ...master-switch transcription factor, Foxp3, which establishes the essential core program that defines Treg cell lineage identity in the thymus and peripheral tissues. Moreover, Foxp3+ Treg cells integrate a variety of inflammatory signals from the tissue microenvironment to engage specialized pathways in order to adapt their suppressive functions in situ. CD4+ Treg cell subsets possess mechanisms to control both gene transcription and mRNA translation. Ultimately, the resulting proteome orchestrates distinct cellular processes that poise Treg cell subsets to respond to inflammatory signals in a timely and context-dependent manner in lymphoid and non-lymphoid tissues for a coordinated modulation of immunity. Thus, understanding how Treg cells control their cellular adaptation in lymphoid and non-lymphoid tissues may reveal therapeutic targets for the treatment of autoimmunity and chronic inflammatory diseases.
Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism ...and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.
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•T cells display metabolic flexibility in response to nutrient limitation•AMPK couples nutrient availability to T cell effector function•T cell metabolic adaptation is AMPKα1-dependent•AMPKα1 is required for primary T cell responses and cellular bioenergetics in vivo
T cells undergo metabolic reprogramming upon activation to fuel T cell growth, proliferation, and effector function. Jones and colleagues show effector T cells adapt their metabolic programs in response to reduced glucose availability, which is regulated by the energy sensor AMPK.
Selective translational control of gene expression is emerging as a principal mechanism for the regulation of protein abundance that determines a variety of functions in both the adaptive immune ...system and the innate immune system. The translation-initiation factor eIF4E acts as a node for such regulation, but non-eIF4E mechanisms are also prevalent. Studies of 'translatomes' (genome-wide pools of translated mRNA) have facilitated mechanistic discoveries by identifying key regulatory components, including transcription factors, that are under translational control. Here we review the current knowledge on mechanisms that regulate translation and thereby modulate immunological function. We further describe approaches for measuring and analyzing translatomes and how such powerful tools can facilitate future insights on the role of translational control in the immune system.
Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy, inducing durable remissions in responding patients. However, they are associated with variable outcomes, spanning from ...disease hyperprogression to complete responses with the onset of immune-related adverse events. The consequences of checkpoint inhibition on Foxp3
regulatory T (T
) cells remain unclear but could provide key insights into these variable outcomes. In this review, we first cover the mechanisms that underlie the development of hot and cold tumour microenvironments, which determine the efficacy of immunotherapy. We then outline how differences in tumour-intrinsic immunogenicity, T-cell trafficking, local metabolic environments and inhibitory checkpoint signalling differentially impair CD8
T-cell function in tumour microenvironments, all the while promoting T
-cell suppressive activity. Finally, we focus on the mechanisms that enable the induction of polyfunctional CD8
T-cells upon checkpoint blockade and discuss the role of ICI-induced T
-cell reactivation in acquired resistance to treatment.
During infections, the timings of effector differentiation of pulmonary immune responses are of paramount importance, as pathogen persistence and unsuppressed inflammation can rapidly lead to a loss ...of function, increased frailty, and death. Thus, both an efficient clearance of the danger and a rapid resolution of inflammation are critical to host survival. We now know that tissue-localized FoxP3
regulatory T cells, a subset of CD4
T cells, are highly attuned to the type of immune response, acquiring unique phenotypic characteristics that allow them to adapt their suppressive functions with the nature of inflammatory cells. To achieve this, activated effector T
cells acquire specialized T
1, T
2, and T
17-like characteristics that allow them to migrate, survive, and time their function(s) through refined mechanisms. Herein, we describe how this process requires a unique developmental path that includes the acquisition of master transcription factors and the expression of receptors adapted to sense local danger signals that are found during pulmonary inflammation. In turn, we offer an overview of how these characteristics promote the capacity of local effector T
cells to proliferate, survive, and display suppressive strategies to resolve lung injury.
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immune-regulating activities in many contexts, such as fetal protection, allograft protection, and cancer progression. ...Clinical trials are currently evaluating IDO inhibition with 1-methyltryptophan in cancer immunotherapy. However, the exact role of tryptophan catabolism by IDO in human cancers remains poorly understood. Here, we review several studies that correlate IDO expression in human cancer samples and tumor-draining lymph nodes, with relevant clinical or immunologic parameters. IDO expression in various histologic cancer types seems to decrease tumor infiltration of immune cells and to increase the proportion of regulatory T lymphocytes in the infiltrate. The impact of IDO on different immune cell infiltration leads to the conclusion that IDO negatively regulates the recruitment of antitumor immune cells. In addition, increased IDO expression correlates with diverse tumor progression parameters and shorter patient survival. In summary, in the vast majority of the reported studies, IDO expression is correlated with a less favorable prognosis. As we may see results from the first clinical trials with 1-methyltryptophan in years to come, this review brings together IDO studies from human studies and aims to help appreciate outcomes from current and future trials. Consequently, IDO inhibition seems a promising approach for cancer immunotherapy.
Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the ...immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.
A progressive waning in Foxp3(+) regulatory T cell (Treg) functions is thought to provoke autoimmunity in the NOD model of type 1 diabetes (T1D). A deficiency in IL-2 is one of the main triggers for ...the defective function of Tregs in islets. Notably, abrogation of the ICOS pathway in NOD neonates or BDC2.5-NOD (BDC2.5) mice exacerbates T1D, suggesting an important role for this costimulatory pathway in tolerance to islet Ags. Thus, we hypothesize that ICOS selectively promotes Foxp3(+) Treg functions in BDC2.5 mice. We show that ICOS expression discriminates effector Foxp3(-) T cells from Foxp3(+) Tregs and specifically designates a dominant subset of intra-islet Tregs, endowed with an increased potential to expand, secrete IL-10, and mediate suppressive activity in vitro and in vivo. Consistently, Ab-mediated blockade or genetic deficiency of ICOS selectively abrogates Treg-mediated functions and T1D protection and exacerbates disease in BDC2.5 mice. Moreover, T1D progression in BDC2.5 mice is associated with a decline in ICOS expression in and expansion and suppression by intra-islet Foxp3(+) Tregs. We further show that the ICOS(+) Tregs, in contrast to their ICOS(-) counterparts, are more sensitive to IL-2, a critical signal for their survival and functional stability. Lastly, the temporal loss in ICOS(+) Tregs is readily corrected by IL-2 therapy or protective Il2 gene variation. Overall, ICOS is critical for the homeostasis and functional stability of Foxp3(+) Tregs in prediabetic islets and maintenance of T1D protection.
Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade ...resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B
, interferon (IFN)-γ
CD8
cytotoxic T cell and circulating regulatory T (T
) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated T
cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ
CD4
T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.
During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to ...infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.
Homeostatic Yin/Yang mechanisms enable the human immune system to eliminate microbes without causing autoimmunity.T cells can become positive effectors or negative regulators (e.g., Tregs) that either control immunity or maintain tolerance. DCs can become either immunogenic to induce T effectors, or tolerogenic to develop Tregs.At steady-state, tolerogenic DC populations and Tregs produce IL-10 and TGF-β. IL-2 is needed for Treg function and fitness, and its production or utilization is often impaired in some autoimmune diseases.Emerging strategies to treat autoimmunity include NPs targeted to DCs or Tregs in vivo; these have the potential to shift immunogenic DCs to tolerogenic DCs to induce and expand Tregs to numbers that might restore normal homeostasis. Biodegradable poly(lactic-co-glycolic acid) NPs loaded with rapamycin can induce tolerogenic DCs and Tregs, and protect mice against some autoimmune diseases (e.g., lupus).Other new therapeutic products to treat specific autoimmune diseases might enhance the activity of cellular regulators of immune and inflammatory responses (e.g., TNFR2 and PPAR α/γ agonists).Some commensal bacteria express cell-surface polysaccharides that can enable tolerogenic DCs to induce Tregs. Obesity alters the microbiome leading to metabolic syndrome and systemic inflammation. The prebiotic olligfructose can restore the lean gut microbiome and, thereby, reduce joint and colon inflammation.
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