Salty Treg cells get out of balance.

Although metabolic rewiring of Treg cells constitutes a hallmark in autoimmune diseases, extrinsic and intrinsic mechanisms that imprint on this re-programming remain poorly understood. In this issue of Cell Metabolism, Côrte-Real and colleagues demonstrate that high salt exposure disturbs the mitochondrial respiration in Treg cells, promoting a pro-inflammatory phenotype, loss of function, and associated breakdown of self-tolerance.

Akt Inhibition Promotes Autophagy and Clearance of Group B Streptococcus from the Alveolar Epithelium.

Group B Streptococcus (GBS) is a gram-positive bacterium that is harmless for healthy individuals but may provoke invasive disease in young infants and immunocompromised hosts. GBS invades the epithelial barriers to enter the bloodstream, and thus strategies that enhance epithelial cell responses may hamper GBS invasion. In the present study, we sought to investigate whether the inhibition of Akt, a kinase that regulates host inflammatory responses and autophagy via suppression of mTOR, can enhance the response of non-phagocytic alveolar epithelial cells against GBS. Treatment of the alveolar epithelial cell line A549 with the Akt inhibitor MK-2206 resulted in the enhanced production of reactive oxygen species and inflammatory mediators in response to GBS. Additionally, Akt inhibition via MK-2206 resulted in elevated LC3II/I ratios and increased autophagic flux in alveolar epithelial cells. Importantly, the inhibition of Akt promoted GBS clearance both in alveolar epithelial cells in vitro and in lung tissue in vivo in a murine model of GBS pneumonia. The induction of autophagy was essential for GBS clearance in MK-2206 treated cells, as knockdown of ATG5, a critical component of autophagy, abrogated the effect of Akt inhibition on GBS clearance. Our findings highlight the role of Akt kinase inhibition in promoting autophagy and GBS clearance in the alveolar epithelium. The inhibition of Akt may serve as a promising measure to strengthen epithelial barriers and prevent GBS invasion in susceptible hosts.

Ablation of NLRP3 inflammasome rewires MDSC function and promotes tumor regression.

Myeloid-derived suppressor cells (MDSCs) are myeloid precursors that exert potent immunosuppressive properties in cancer. Despite the extensive knowledge on mechanisms implicated in mobilization, recruitment, and function of MDSCs, their therapeutic targeting remains an unmet need in cancer immunotherapy, suggesting that unappreciated mechanisms of MDSC-mediated suppression exist. Herein, we demonstrate an important role of NLRP3 inflammasome in the functional properties of MDSCs in tumor-bearing hosts. Specifically, Nlrp3-deficient mice exhibited reduced tumor growth compared to wild-type animals and induction of robust anti-tumor immunity, accompanied by re-wiring of the MDSC compartment. Interestingly, both monocytic (M-MDSCs) and granulocytic (G-MDSCs) subsets from Nlrp3-/- mice displayed impaired suppressive activity and demonstrated significant transcriptomic alterations supporting the loss-of-function and associated with metabolic re-programming. Finally, therapeutic targeting of NLRP3 inhibited tumor development and re-programmed the MDSC compartment. These findings propose that targeting NLRP3 in MDSCs could overcome tumor-induced tolerance and may provide new checkpoints of cancer immunotherapy.

Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle.

Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to "ex-Treg" cells and the "fragile" Treg cells in which FOXP3 expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.

Decoding the Myeloid-Derived Suppressor Cells in Lymphoid Malignancies.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid precursors which emerged as a potent regulator of the immune system, exerting suppressive properties in diverse disease settings. In regards to cancer, MDSCs have an established role in solid tumors; however, their contribution to immune regulation during hematologic malignancies and particularly in lymphomas remains ill-defined. Herein focused on lymphoma, we discuss the literature on MDSC cells in all histologic types, and we also refer to lessons learned by animal models of lymphoma. Furthermore, we elaborate on future directions and unmet needs and challenges in the MDSC field related to lymphoma malignancies which may shed light on the complex nature of the immune system in malignancies.