SciencetRNA's umbrella to avoid excessive stress of T cell immunity

Written | Sister Xian, when exposed to external antigens, T cells are rapidly activated, and their transition from a resting state to a proliferating state requires tremendous changes in cell metabolism, especially glycolysis, glutamine decomposition and increased mitochondrial metabolism.
To produce high levels of energy and biosynthetic precursors, so as to meet the growth and clonal expansion of T cells, and subsequent differentiation
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The increase in T cell metabolism depends on the metabolic enzymes produced by translation bursts, and the production of clonal T cell progeny and the protein components of their cytokines [1, 2]
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Paradoxically, however, rapid T cell expansion is also accompanied by an increase in the concentration of reactive oxygen species (ROS)
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As a byproduct of enhanced mitochondrial metabolism, ROS can act as the second messenger of T cell receptor (TCR) signals, activate important transcription factors during T cell activation, and promote T cell proliferation
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However, ROS generated during T cell activation can also cause tRNA fragmentation, translation inhibition and the formation of stress granules [3, 4]
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Among them, tRNA fragmentation can inhibit the overall translation of proteins, inhibit the translation of specific target mRNAs through similar effects of microRNA, and regulate the stability of mRNA
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Fragments derived from tRNA (tRF), especially tiRNA with a size close to half of tRNA (30-40 nt), are usually produced under stress and form stress particles (by blocking the translation initiation factor to inhibit the overall translation of the cytoplasmic RNA protein complex (Things) [5], but at present, the cause of tRNA fragmentation in the process of T cell activation is still unknown
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At the same time, studies have found that in the absence of antioxidants, the accumulation of ROS can impair metabolic reprogramming and T cell proliferation [6]
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This suggests that in order to maintain the signal activity of ROS, the protective mechanism against oxidative stress may not only occur by simply reducing the level of ROS in T cells
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Genetic screening revealed a mutation called elektra, which can cause immunodeficiency in mice through a single loss-of-function missense mutation in the Schlafen2 (Slfn2) gene [7]
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SLFN2 is a member of the Schlafen gene family, which mainly exists in mammals.
This family was first identified in 1998 when the regulators of thymocyte development were screened.
Due to the lack of homology with other protein families, the function of Schlafen protein and The mechanism of action is still unclear
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Studies have found that Slfn2 mutations are related to impaired T cell activation.
However, whether Slfn2 directly regulates T cell functions and how to regulate it is still unclear
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Based on the above, the Bruce Beutler team from the University of Texas Southwestern Medical Center recently published an article titled SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity in Science, providing TCR and co- The evidence that stimulated receptors are involved in the oxidative stress response of T cells is characterized by the induction of tiRNA, translational inhibition, and the formation of stress granules; a protective mechanism for SLFN2 to protect tRNA from oxidative stress-induced cleavage is described.
This prevents the translational inhibition of ROS generated when T cells are activated, thereby providing further support for the key role of SLFN family members in RNA and translation regulation, and thus reveals the necessary mechanism for T cell-mediated immunity— -T cells rely on SLFN2 to maintain their rapid and abundant protein translation capabilities
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In this paper, the researchers first constructed CD4+ and CD8+ T cell conditional knockout Slfn2 mouse models.
The experiment found that T cell-specific SLFN2 deficient (Slfn2–/– T cell) mice are immune to T cell dependent antigens and small Murine cytomegalovirus infection showed impaired humoral and cellular immune responses, suggesting that the role of SLFN2 in T cells is necessary for T cell-mediated immunity
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At the same time, the researchers also found that experimental autoimmune encephalomyelitis (EAE, multiple sclerosis mouse model) in Slfn2–/– T-cell mice is less severe, suggesting that SLFN2 is effective in this autoimmune environment.
T cell function is also crucial
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Furthermore, the researchers found that the impaired T cell function caused by T cell-specific SLFN2 deficiency stems from the impaired T cell proliferation response to TCR stimulation, although TCR signaling events are normally induced in Slfn2–/– T cells
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It is known that stimulation of T cells by TCR can up-regulate the transcription and translation of the high-affinity IL-2 receptor (IL-2R), induce IL-2 secretion and response to IL-2, resulting in autocrine-paracrine signals and T Cell proliferation
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Although this study found that the IL-2 produced by Slfn2–/– T cells is not affected, it cannot proliferate under the stimulation of exogenous IL-2
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Further experiments showed that the IL-2R signaling pathway was impaired in Slfn2–/– T cells, and the expression of IL-2Rβ and IL-2Rγ on the cell surface was significantly reduced, which is directly related to the impaired translation in SLFN2-deficient T cells ——Control T cells can initiate a translation burst within 8 to 24 hours after TCR activation, but this translation is significantly weakened in SLFN2-deficient T cells, which may lead to cell proliferation failure
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Furthermore, the researchers found that SLFN2 can directly bind to tRNA and form a stable complex.
However, unlike SLFN11 and SLFN13, SLFN2 does not cleave due to the deletion of two acidic residues important for ribonuclease (RNase) activity.
tRNA
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On the contrary, the researchers found abnormal accumulation of tRNA fragments and reduction of the parent's full-length tRNA in SLFN2-deficient T cells, and these phenomena became more obvious after T cell activation
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In addition, after antigen stimulation, although the amount of ROS produced by Slfn2–/– T cells was similar to that of control T cells, when antioxidants were given, the accumulation of tiRNA in Slfn2–/– T cells was significantly reduced; on the contrary, When unstimulated T cells are stimulated by H2O2, the tiRNA in Slfn2–/– T cells accumulates excessively, which suggests that tRNA in SLFN2-deficient T cells are more sensitive to oxidative stress and easier to be lysed
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This, in turn, is closely related to the decrease in translation in Slfn2–/– T cells
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At the same time, the research results show that the antioxidant inhibition of ROS in activated SLFN2-deficient T cells is sufficient to greatly reduce the abnormal accumulation of tiRNA and subsequent translation inhibition and stress particle assembly, thereby increasing activation-induced SLFN2-deficient T cells Of proliferation
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In activated T cells, oxidative stress is a necessary factor for the induced expression of ribonuclease ANG, and ANG is the main enzyme that cleaves to produce tiRNA during oxidative stress
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Both in vitro and in vivo experiments have shown that ANG mediates the lysis of tRNA in SLFN2-deficient T cells, leading to impaired translation and cell proliferation under TCR stimulation
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Knockdown of ANG or overexpression of ANG inhibitor RNH1 in Slfn2–/– T cells can reduce the accumulation of tiRNA and increase the rate of intracellular protein translation
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This indicates that SLFN2 can directly inhibit the cleavage of tRNA by ANG, and the direct binding of SLFN2 and tRNA is a necessary condition to protect tRNA from being cleaved, so as to ensure the normal translation of T cell activation
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In summary, this study reveals an important protective mechanism of T cell immunity—SLFN2 protects T cells from excessive stress during immune activation, thereby promoting the necessary up-regulation of protein translation
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SLFN2 can bind to and protect tRNA, an important molecule in the process of mRNA translation, from fragmentation activated by stress
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If SLFN2 is defective, excessive tRNA fragmentation will reduce overall translation, especially the translation of key cytokine receptor proteins that are important for T cell activation
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This expands the function of tRNA fragmentation, and clarifies the role of SLFN2 in preventing fragmentation and achieving immune function
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Original link: https://doi.
org/10.
1126/science.
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