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The metabolism of T-lymphocytes has recently emerged as a pivotal area of investigation, offering insights into the supra-genic modulations that can influence the genetic mechanisms underlying lymphocyte clustering processes. Furthermore, it has become a crucial aspect in understanding lymphocyte plasticity within the immune microenvironment, both in physiological and pathological contexts. T-lymphocyte metabolism has recently emerged as a pivotal factor in both targeted therapy and the genetic signature of the T-lymphocyte, as a result of its influence on gatekeeper processes. From this perspective, the interconnections between the metabolic processes traditionally associated with energy production and the capacity to influence the genetic fate of the T lymphocyte have identified purine metabolism and nuclear/cytoplasmic signaling as pivotal elements in comprehending the intricacies of these molecular phenomena. The two aspects of purine metabolism and metabolic/molecular control of the nuclear envelope have been the subject of a number of significant studies published in recent years. However, from a certain perspective, the existing evidence remains sparse and inconclusive, hindering a comprehensive understanding of the subject matter. In this review, we endeavor to establish a connection between these aspects for the first time and to present a review of the molecular, immunological and genetic events that determine how these aspects, which have hitherto received insufficient attention, may represent a new avenue for lymphocyte reprogramming in the therapeutic field. This will be achieved by understanding the connections between nuclear control and purine flux within and outside the cell. [ABSTRACT FROM AUTHOR]

The CD4+ T‐cell population plays a vital role in the adaptive immune system by coordinating the immune response against different pathogens. A significant transformation occurs in CD4+ cells during an immune response, as they shift from a dormant state to an active state. This transformation leads to extensive proliferation, differentiation, and cytokine production, which contribute to regulating and coordinating the immune response. Th17 and Treg cells are among the most intriguing CD4+ T‐cell subpopulations in terms of genetics and metabolism. Gene expression modulation processes rely on and are linked to metabolic changes in cells. Lactylation is a new model that combines metabolism and gene modulation to drive Th17/Treg differentiation and functional processes. The focus of this review is on the metabolic pathways that impact lymphocyte gene modulation in a functionally relevant manner. [ABSTRACT FROM AUTHOR]

The Th17+ arrangement is critical for orchestrating both innate and acquired immune responses. In this context, the serum and glucocorticoid regulated kinase 1 (SGK1) exerts a key role in the governance of IL-23R-dependent Th17+ maturation, through the phosphorylation-dependent control of FOXO1 localization. Our previous work has shown that some of the SGK1-key functions are dependent on RAN-binding protein 1 (RANBP1), a terminal gene in the nuclear transport regulation. Here, we show that RANBP1, similarly to SGK1, is modulated during Th17+ differentiation and that RANBP1 fluctuations mediate the SGK1-dependent effects on Th17+ maturation. RANBP1, as the final effector of the SGK1 pathway, affects FOXO1 transport from the nucleus to the cytoplasm, thus enabling RORgt activation. In this light, RANBP1 represents the missing piece, in an essential and rate-limiting manner, underlying the Th17+ immune asset. [ABSTRACT FROM AUTHOR]

The Th17 + arrangement is critical for orchestrating both innate and acquired immune responses. In this context, the serum and glucocorticoid regulated kinase 1 (SGK1) exerts a key role in the governance of IL-23R-dependent Th17 + maturation, through the phosphorylation-dependent control of FOXO1 localization. Our previous work has shown that some of the SGK1-key functions are dependent on RAN-binding protein 1 (RANBP1), a terminal gene in the nuclear transport regulation. Here, we show that RANBP1, similarly to SGK1, is modulated during Th17 + differentiation and that RANBP1 fluctuations mediate the SGK1-dependent effects on Th17 + maturation. RANBP1, as the final effector of the SGK1 pathway, affects FOXO1 transport from the nucleus to the cytoplasm, thus enabling RORγt activation. In this light, RANBP1 represents the missing piece, in an essential and rate-limiting manner, underlying the Th17 + immune asset., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brescia, Dattilo, D’Antona, Chiarella, Tallerico, Audia, Rocca, Iuliano, Trapasso, Perrotti and Amato.)