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Key Points Regulatory T (T Reg ) cells can be induced in both the thymus and the periphery. Together, these T Reg cells constitute the peripheral T Reg cell pool, which can be divided into 'central' T Reg cells, 'effector' T Reg cells and 'tissue-resident' T Reg cells. Effector T Reg cells show plasticity and heterogeneity, with distinct phenotypic and functional profiles being induced in response to different microenvironments. Non-lymphoid tissues contain T Reg cells. This population is likely to be a heterogeneous mixture of transiently migrating effector T Reg cells and long-term resident T Reg cells with additional local functions. T Reg cell homeostasis is a dynamic process, with a stable population size being maintained through a balance of proliferation and apoptosis. The predominant central T Reg cell population size is modulated by pro-apoptotic changes (forkhead box P3 (FOXP3)-mediated phosphorylation of B-cell lymphoma 2-interacting mediator of cell death (BIM)) and pro-survival responses (interleukin-2 (IL-2)-mediated upregulation of induced myeloid cell leukaemia 1 (MCL1)). Subpopulations of T Reg cells can have distinct molecular pathways of homeostasis. T Reg cell and conventional T cell subsets can act in competition with each other for limiting IL-2 and other homeostatic mediators. Dysregulation of T Reg cell homeostasis through competition can result in immune-mediated disease, including graft-versus-host disease. Regulatory T (T Reg ) cells are crucial for maintaining immune homeostasis in the body, with recent data showing that distinct T Reg cell subsets become specialized to function in different tissues. Here, Liston and Gray highlight the need to regulate the number and function of the T Reg cells themselves, and they describe the dynamic processes that achieve this homeostasis and functional specialization of T Reg cell subsets. Regulatory T (T Reg ) cells constitute an essential counterbalance to adaptive immune responses. Failure to maintain appropriate T Reg cell numbers or function leads to autoimmune, malignant and immunodeficient conditions. Dynamic homeostatic processes preserve the number of forkhead box P3-expressing (FOXP3 + ) T Reg cells within a healthy range, with high rates of cell division being offset by apoptosis under steady-state conditions. Recent studies have shown that T Reg cells become specialized for different environmental contexts, tailoring their functions and homeostatic properties to a wide range of tissues and immune conditions. In this Review, we describe new insights into the molecular controls that maintain the steady-state homeostasis of T Reg cells and the cues that drive T Reg cell adaptation to inflammation and/or different locations. We highlight how differing local milieu might drive context-specific T Reg cell function and restoration of immune homeostasis, and how dysregulation of these processes can precipitate disease.

\"Encourages children to show love and support for each other and to consider each other's well-being in their everyday actions.\"--Provided by publisher.

Multipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies. Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.

\"In space, size matters. Boomers. Ships of the Line. Star Destroyers. The bigger the ship, the better the bang. From the dawn of history onward, commanding the most powerful ship around has been a dream of admirals, sultans, emperors, kings, generalissimos, and sea captains everywhere. For what the intimidation factor alone doesn't achieve, a massive barrage from super-weapons probably will. Thus it was, and ever shall be, even into the distant future. From the oceans of Earth, to beneath the ice of Europa, to the distant reaches of galactic empires, it is the great warships and their crews that sometimes keep civilization safe for the rest of us -- but sometimes become an extinction-level event in and of themselves\"--Back cover.

The signals controlling T reg cell homeostasis and survival are still being determined. Liston and colleagues demonstrate that peripheral T reg cells depend critically on IL-2 and the survival factor Mcl-1 but not on Bcl-2. Foxp3 + regulatory T (T reg ) cells are a crucial immunosuppressive population of CD4 + T cells, yet the homeostatic processes and survival programs that maintain the T reg cell pool are poorly understood. Here we report that peripheral T reg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2–dependent and costimulation-dependent process. By contrast, excess T reg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-x L and Bcl-2 were dispensable for survival of T reg cells, whereas Mcl-1 was critical for survival of T reg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which T reg cells maintain homeostasis via critical survival pathways.

The persistence of latently infected CD4 + T-cells in people with HIV (PWH) on suppressive antiretroviral therapy (ART) is the major barrier to an HIV cure. We investigated the impact of two classes of pro-apoptotic drugs, phosphoinositide-3 kinases (PI3K) inhibitors or the B cell lymphoma 2 (Bcl-2) inhibitor venetoclax on depletion of latently infected CD4 + T-cells when administered ex vivo either alone or in combination with a latency reversing agents (LRA) to induce expression of pro-apoptotic viral proteins. We quantified cell death in three latently infected cell lines (J-Lat clones) and the parental cell line (Jurkat) using a live dead stain and flow cytometry. Using CD4 + T-cells isolated from blood from PWH on ART, we quantified intracellular HIV RNA, integrated HIV DNA and intact proviral DNA using quantitative PCR. In the Jat10.6 latently infected cell line, the combination of an LRA with either a PI3K inhibitor or venetoclax, compared to an LRA alone resulted in higher levels of cell death. Using CD4 + T-cells from PWH on ART, there was a significant decrease in HIV DNA following administration of wortmannin (a pan-PI3K inhibitor), venetoclax (a Bcl2 inhibitor) and JQ1 (an LRA) when administered alone. There was minimal additional effect on reservoir reduction following the addition of an LRA with a pro-apoptotic drug, compared to either an LRA or pro-apoptotic drug alone. However, when CD4 + T-cells from PWH on ART were treated with LRAs combined with a PI3K inhibitor, the fold increase in cell associated unspliced HIV RNA correlated with the decline in HIV DNA. Overall, reduction in the HIV reservoir by LRAs could be further enhanced in the presence of pro-apoptotic drugs, but the magnitude of the effect was modest, was dependent on the in vitro model used and for PI3K inhibitors, depended on the potency of latency reversal. These results are consistent with minimal additional efficacy in reservoir reduction when combining currently available LRAs and either PI3K inhibitors or venetoclax.

The use of animal models in brain aging research has led to numerous fundamental insights into the neurobiological processes that underlie changes in brain function associated with normative aging. Macaque monkeys have become the predominant nonhuman primate model system in brain aging research due to their striking similarities to humans in their behavioral capacities, sensory processing abilities, and brain architecture. Recent public concern about nonhuman primate research has made it imperative to attempt to clearly articulate the potential benefits to human health that this model enables. The present review will highlight how nonhuman primates provide a critical bridge between experiments conducted in rodents and development of therapeutics for humans. Several studies discussed here exemplify how nonhuman primate research has enriched our understanding of cognitive and sensory decline in the aging brain, as well as how this work has been important for translating mechanistic implications derived from experiments conducted in rodents to human brain aging research.

Intrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function. Genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. Deleting VDAC2 phenocopied the loss of BAX in impairing both the killing of tumor cells by anti-cancer agents and the ability to suppress tumor formation. Together, our studies show that efficient BAX-mediated apoptosis depends on VDAC2, and reveal a striking difference in how BAX and BAK are functionally impacted by their interactions with VDAC2. BAX and BAK are pro-apoptotic proteins whose activity is essential for the action of many anti-cancer drugs and to suppress tumorigenesis. Here, the authors perform a genome-wide CRISPR/Cas9 screen and identify VDAC2 as a promoter of BAX-mediated apoptosis that is important for an efficient chemotherapeutic response and to suppress tumor formation.