Deacetylase Sirtuin 1 mitigates type I IFN- and type II IFN-induced signaling and antiviral immunity.

Type I and type II IFNs are important immune modulators in both innate and adaptive immunity. They transmit signaling by activating JAK-STAT pathways. Sirtuin 1 (SIRT1), a class III NAD+-dependent deacetylase, has multiple functions in a variety of physiological processes. Here, we characterized the novel functions of SIRT1 in the regulation of type I and type II IFN-induced signaling. Overexpression of SIRT1 inhibited type I and type II IFN-induced interferon-stimulated response element activation. In contrast, knockout of SIRT1 promoted type I and type II IFN-induced expression of ISGs and inhibited viral replication. Treatment with SIRT1 inhibitor EX527 had similar positive effects. SIRT1 physically associated with STAT1 or STAT3, and this interaction was enhanced by IFN stimulation or viral infection. By deacetylating STAT1 at K673 and STAT3 at K679/K685/K707/K709, SIRT1 downregulated the phosphorylation of STAT1 (Y701) and STAT3 (Y705). Sirt1+/- primary peritoneal macrophages and Sirt1+/- mice exhibited enhanced IFN-induced signaling and antiviral activity. Thus, SIRT1 is a novel negative regulator of type I and type II IFN-induced signaling through its deacetylase activity.IMPORTANCESIRT1 has been reported in the precise regulation of antiviral (RNA and DNA) immunity. However, its functions in type I and type II IFN-induced signaling are still unclear. In this study, we deciphered the important functions of SIRT1 in both type I and type II IFN-induced JAK-STAT signaling and explored the potential acting mechanisms. It is helpful for understanding the regulatory roles of SIRT1 at different levels of IFN signaling. It also consolidates the notion that SIRT1 is an important target for intervention in viral infection, inflammatory diseases, or even interferon-related therapies.

CBX4 promotes antitumor immunity by suppressing Pdcd1 expression in T cells.

E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from the knockout mice, which was accompanied by a functional defect in response to T-cell receptor (TCR) stimulation. In support of a direct link between CBX4 and PD-1, Cbx4 overexpression resulted in the downregulation of Pdcd1 expression. Epigenetic analyses indicated that Cbx4 deficiency leads to diminished accumulation of inhibitory histone modifications at conserved region (CR)-C and CR-B sites of the Pdcd1 promoter, namely mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3). Moreover, inhibition of either the E3 ligase activity of polycomb-repressive complexes 1 (PRC1) or the methyltransferase activity of polycomb-repressive complexes 2 (PRC2) restores Pdcd1 expression in Cbx4-transfected cells. Cumulatively, this study reveals a novel function of CBX4 in the regulation of T-cell function and expands our understanding of the epigenetic control of Pdcd1 expression.

Deubiquitinase USP47 attenuates virus-induced type I interferon signaling.

The innate immune responses are tightly regulated to ensure effective clearance of invading pathogens and avoid excessive inflammation. Ubiquitination and deubiquitination are important post-translational modifications in antiviral immune responses. Here, we discovered deubiquitinase USP47 as a novel negative immune system regulator. Overexpression of USP47 repressed Sendai virus, poly(I:C) and poly(dA:dT)-induced ISRE and IFN-ß activation, along with reduced IFNB1 transcription and enhanced viral replication. Knockdown of USP47 expression had the opposite effects. Dual-luciferase and phosphorylation assays showed that USP47 targeted downstream of MAVS and upstream of TBK1. Additional co-immunoprecipitation assays suggested that USP47 interacted with TRAF3 and TRAF6. Importantly, USP47 removed K63-linked polyubiquitin chains from TRAF3 and TRAF6. Hence, we describe a novel modulator of the antiviral innate immune response, USP47, which removes K63-linked polyubiquitins from TRAF3 and TRAF6, leading to reduced type I IFN signaling.

Prostaglandin E2-Induced AKT Activation Regulates the Life Span of Short-Lived Plasma Cells by Attenuating IRE1α Hyperactivation.

The mechanism regulating the life span of short-lived plasma cells (SLPCs) remains poorly understood. Here we demonstrated that the EP4-mediated activation of AKT by PGE2 was required for the proper control of inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) hyperactivation and hence the endoplasmic reticulum (ER) homeostasis in IgM-producing SLPCs. Disruption of the PGE2-EP4-AKT signaling pathway resulted in IRE1α-induced activation of JNK, leading to accelerated death of SLPCs. Consequently, Ptger4-deficient mice (C57BL/6) exhibited a markedly impaired IgM response to T-independent Ags and increased susceptibility to Streptococcus pneumoniae infection. This study reveals a highly selective impact of the PGE2-EP4 signal on the humoral immunity and provides a link between ER stress response and the life span of SLPCs.

Up-regulated DNA-binding inhibitor Id3 promotes differentiation of regulatory T cell to influence antiviral immunity in chronic hepatitis B virus infection.

AIM: Elevated Treg is relevant to persistent HBV infection, and the regulatory mechanism of Treg levels remains unclear. E proteins are important transcriptional regulators and could be antagonized by inhibitors of DNA-binding (Id) 1-4. We aim to clarify the role of Ids during HBV infection. MAIN METHODS: Changes of Ids and their relationship with Treg were investigated in both HBV transfection model and hepatitis B patients. Significance of Ids was studied by in vitro Treg differentiation induction with Id inhibited or over-expressed. The role of inflammatory cytokines for Id was studied by co-culture. RNA-Seq was conducted to explore the differentially expressed genes in Id-overexpressed CD4 T cells upon Treg differentiation induction conditions. KEY FINDINGS: Id-overexpressed mice attenuated virus clearance in HBV transfection model. In the HBV transfection mouse model, Tregs were up-regulated, with Id3 increased in Treg as well. Clinically, circulating Tregs in chronic hepatitis B (CHB) patients were elevated, and elevated Id3 transcriptional levels were positively correlated with Tregs. IL-1ß could up-regulate Id3 in Treg cells induced in vitro. RNA-Seq revealed that increased Id could cause a series of signaling pathway changes during Treg differentiation. SIGNIFICANCE: Id3 is elevated during HBV infection to ease Treg differentiation, and the antiviral immunity is influenced that make the infection to develop into chronic state.

The essential role of PRAK in tumor metastasis and its therapeutic potential.

Metastasis is the leading cause of cancer-related death. Despite the recent advancements in cancer treatment, there is currently no approved therapy for metastasis. The present study reveals a potent and selective activity of PRAK in the regulation of tumor metastasis. While showing no apparent effect on the growth of primary breast cancers or subcutaneously inoculated tumor lines, Prak deficiency abrogates lung metastases in PyMT mice or mice receiving intravenous injection of tumor cells. Consistently, PRAK expression is closely associated with metastatic risk in human cancers. Further analysis indicates that loss of function of PRAK leads to a pronounced inhibition of HIF-1α protein synthesis, possibly due to reduced mTORC1 activities. Notably, pharmacological inactivation of PRAK with a clinically relevant inhibitor recapitulates the anti-metastatic effect of Prak depletion, highlighting the therapeutic potential of targeting PRAK in the control of metastasis.

Frequency-modulated continuous-wave laser ranging using low-duty-cycle signals for the applications of real-time super-resolved ranging.

A frequency-modulated continuous-wave laser ranging method using low-duty-cycle linear-frequency-modulated (LFM) signals is proposed. A spectrum consisting of a dense Kronecker comb is obtained so that the frequency of the beat signal can be measured with finer resolution. Since the dense comb is provided, super-resolved laser ranging can be achieved using a single-parametric frequency estimation method. Therefore, the run times of the estimation are reduced which promises real-time applications. A proof-of-concept experiment is carried out, in which an LFM signal with a bandwidth of 5 GHz and a duration of 1 µs is used. The duty-cycle of the LFM signal is 10%. The time delay of a scanning variable optical delay line is obtained in real time from the frequency of the highest comb tooth, of which the measurement resolution is 20 ps. Moreover, a single-parametric nonlinear least squares method is used to fit the envelope so that the time delay can be estimated with super-resolution. The standard deviation of the estimation displacements is 2.3 ps, which is 87 times finer than the bandwidth-limited resolution (200 ps). Therefore, the variation of the time delay can be precisely monitored. The proposed method may be used to achieve real-time high-resolution laser ranging with low-speed electronic devices.

Correlation of the levels of DNA-binding inhibitor Id3 and regulatory T cells with SLE disease severity.

E proteins, a subset of basic helix-loop-helix (bHLH) proteins, are transcription activators and their functions are inhibited by DNA-binding inhibitor (Id) 1-4. Studies have shown that Treg levels are decreased in Id3 knockout mice. Mice over-expressing Id1 in CD4 T cells possessed a greater number of regulatory T cells (Treg) and exhibited attenuated experimental autoimmune encephalomyelitis (EAE). The significance of Id proteins in human systemic lupus erythematosus (SLE) remains unclear. In this study, we systematically analyzed Id transcription in naïve, memory CD4 cells and regulatory T cells in peripheral blood mononuclear cells (PBMCs) in patients with active or inactive SLE. In parallel, Treg subsets in PBMCs were analyzed using different strategies. Id expression levels were correlated with Treg numbers as well as clinical indicators. We found that Id genes expressed in human peripheral CD4 cells were mainly Id2 and Id3. Id3 levels were significantly elevated in CD4+CD25hi T cells of patients with active SLE. Likewise, Id3 levels were positively correlated with increased CD4+FoxP3+ and CD4+Helios+FoxP3+ Treg cells in these patients. Id3 levels were found to be positively correlated with erythrocyte sedimentation rate (ESR), lupus anticoagulant (LAC), ribosomal antibody and SLE Disease Activity Index (SLEDAI) in patients with active SLE. Mice overexpressing Id1 in CD4+ T cells possessed significantly higher Treg levels in spleen and lower autoantibody concentrations in serum. Our results suggest that during the pathogenesis of SLE, up-regulation of Id3 can promote Treg differentiation to play an inhibitory effect on autoimmune responses.

Inhibition of E protein activity facilitates the quiescence exit of naïve CD4+ T cells through modulating PI3K-AKT signaling and TCR microcluster formation.

Many aspects remain elusive of the mechanisms governing T cell quiescence. Here we show that E protein activity helps to establish a quiescent program in naïve T cells. Decreased E protein activity, as the consequence of enforced expression of an Id1 transgene, led to the accumulation of CD4+CD44hi T cells. The naïve CD4+ T cells from this transgenic strain mounted a vigorous proliferative response upon TCR stimulation, as a result of direct inhibition of E protein activity. Transcriptome analyses demonstrated that Id1-tg naïve CD4+ T cells exhibited a transcriptional profile characteristic of activated CD4+ T cells, with particular enrichment in the gene set related to PI3K-AKT signaling. Western blot analysis confirmed low but constitutive activation of this pathway. Moreover, the Id1-tg CD4+ T cells displayed enhanced formation of TCR microcluster. Taken together, these data support that downregulation of E protein activity facilitates the exit of naïve T cells from quiescence.

TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.

Thymic natural killer T (NKT)2 cells are a subset of invariant NKT cells with PLZFhiGATA3hiIL-4+. The differentiation of NKT2 cells is not fully understood. In the present study, we report an important role of TRAF3-interacting protein 3 (TRAF3IP3) in the functional maturation and expansion of committed NKT2s in thymic medulla. Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells, decreased IL-4-producing peripheral iNKTs, and defects in response to α-galactosylceramide. Positive selection and high PLZF expression in CD24+CD44- and CCR7+CD44- immature iNKTs were not affected. Only CD44hiNK1.1- iNKTs in Traf3ip3-/- mice showed reduced expression of Egr2, PLZF, and IL-17RB, decreased proliferation, and reduced IL-4 production upon stimulation. This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs, and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation. LTßR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation. These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.

A wave of Foxp3+ regulatory T cell accumulation in the neonatal liver plays unique roles in maintaining self-tolerance.

Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period. Regulatory T cells (Tregs) are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses. The features of Tregs in the neonatal liver under steady-state conditions are not well understood. The present study aimed to investigate the phenotype, functions, and significance of neonatal Tregs in the liver. We found a wave of thymus-derived Treg influx into the liver during 1-2 weeks of age. Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder. More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation, and the liver Tregs acquired stronger suppressive functions. The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγ and T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses. The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.

Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells.

To date, IgG in the tumor microenvironment (TME) has been considered a product of B cells and serves as an antitumor antibody. However, in this study, using a monoclonal antibody against cancer-derived IgG (Cancer-IgG), we found that cancer cells could secrete IgG into the TME. Furthermore, Cancer-IgG, which carries an abnormal sialic acid modification in the CH1 domain, directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4+ and CD8+ T-cell infiltration into tumor tissues. Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins (Siglecs) on effector CD4+ and CD8+ T cells. Importantly, we show that several Siglecs are overexpressed on effector T cells from cancer patients, but not those from healthy donors. These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs, which may serve as potential checkpoint proteins and mediate tumor immune evasion.

Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence.

Although autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are frequently associated with premature aging of the thymus, a direct link is missing between autoimmunity and thymic atrophy. Here we monitored the progression of thymic involution in Aire-deficient mice, in which defective negative selection causes spontaneous and progressive development of autoimmunity. In young and middle-aged mice, Aire deficiency appeared to be protective as supported by the reduced ß-gal+ epithelial cells and the enhanced thymic output. However, once the autoimmune phenotype was fully developed in aged Aire-deficient mice, their thymuses underwent accelerated involution. In comparison to the age-matched wildtype littermates, old Aire-deficient mice showed lower numbers of total thymocytes and recent thymic emigrants but more ß-gal+ thymic epithelial cells. This phenomenon may partly be attributable to the increased number of activated Th1 cells homing to the thymus. This speculation was further supported by the enhanced thymic aging following repeated challenges with complete Freund's adjuvant immunization. Taken together, the present study highlights a unique mechanism by which autoimmunity facilitates the senescence of thymic epithelial cells through returning Th1 cells.

CCR2 Signal Facilitates Thymic Egress by Priming Thymocyte Responses to Sphingosine-1-Phosphate.

The signal mediated by sphingosine-1-phosphate receptor 1 (S1P1) is essential but seemingly insufficient for thymic export of newly generated T cells. Here, we reported the identification of CCR2 as an additional regulator of this process. CCR2 showed a markedly increased expression in the most mature subset of single-positive (SP) thymocytes. Its deficiency led to a reduction of recent thymic emigrants in the periphery and a simultaneous accumulation of mature SP cells in the thymus. The CCR2 signaling promoted thymic emigration primarily through modulating the chemotactic responses to S1P1 engagement. On the one hand, the chemokinesis induced by CCR2 activation endowed thymocytes with enhanced capacity to respond to S1P-induced migration. On the other hand, CCR2 signaling through Stat3 augmented forkhead box O1 activity, leading to increased expression of S1P1. Taken together, the present study highlights a unique and novel function of CCR2 signaling in the regulation of thymic egress.

Transcriptome analysis identifies the potential roles of long non-coding RNAs during parainfluenza virus infection.

Parainfluenza virus infection is a common respiratory illness in children. Although lncRNAs are novel regulators of virus-induced innate immunity, a systemic attempt to characterize the differential expression of lncRNAs upon parainfluenza virus infection is lacking. In this report, we identify 207 lncRNAs and 166 mRNAs differentially expressed in SeV-infected HEK293T cells by microarray. The functional annotation analysis reveals that differentially regulated transcripts are predominantly involved in the host antiviral response pathway. The lncRNAs with the potential to regulate SeV-induced antiviral response are identified by building the lncRNA-mRNA coexpression network. Furthermore, silencing lncRNA ENST00000565297 results in reduced type I IFN signaling upon SeV infection. These catalogs may facilitate future analysis of the functions of lncRNAs in innate immunity and related diseases.

Recirculating Th2 cells induce severe thymic dysfunction via IL-4/STAT6 signaling pathway.

Thymic involution happened early in life, but a certain ratio of activated CD4+ T cells will persistently recirculate into the thymus from the periphery and it have been suggested to be able to inhibit the development of embryonic thymocytes. Our present study was aimed to elucidate the specific mechanism how activated CD4+ T cells could influence upon developing thymocytes by using fetal thymic organ culture (FTOC) and kidney capsule transplantation. Our results demonstrated that Th2 cells were found to play a fundamental role in the inhibition of embryonic thymocyte development since a very low concentration of Th2 cells could obviously reduce the total number of thymocytes. And this effect was not tenable in other Th cell type. Notably, IL-4, the major cytokine secreted by Th2 cells, was suggested the key factor playing the inhibition role. In addition to reduced cell population, the proportion of double positive (DP) T cells was also heavily decreased. Furthermore, we demonstrated that it was the downstream effector signal transducer and activator of transcription 6 (STAT6) of IL-4 partially manipulate this inhibition. Together, these findings reveal a novel influence of Th2 cells re-entering the thymus on thymic involution.

USP7-TRIM27 axis negatively modulates antiviral type I IFN signaling.

Ubiquitination and deubiquitination are important post-translational regulatory mechanisms responsible for fine tuning the antiviral signaling. In this study, we identified a deubiquitinase, the ubiquitin-specific peptidase 7/herpes virus associated ubiquitin-specific protease (USP7/HAUSP) as an important negative modulator of virus-induced signaling. Overexpression of USP7 suppressed Sendai virus and polyinosinic-polycytidylic acid and poly(deoxyadenylic-deoxythymidylic)-induced ISRE and IFN-ß activation, and enhanced virus replication. Knockdown or knockout of endogenous USP7 expression had the opposite effect. Coimmunoprecipitation assays showed that USP7 physically interacted with tripartite motif (TRIM)27. This interaction was enhanced after SeV infection. In addition, TNF receptor-associated factor family member-associated NF-kappa-B-binding kinase (TBK)-1 was pulled down in the TRIM27-USP7 complex. Overexpression of USP7 promoted the ubiquitination and degradation of TBK1 through promoting the stability of TRIM27. Knockout of endogenous USP7 led to enhanced TRIM27 degradation and reduced TBK1 ubiquitination and degradation, resulting in enhanced type I IFN signaling. Our findings suggest that USP7 acts as a negative regulator in antiviral signaling by stabilizing TRIM27 and promoting the degradation of TBK1.-Cai, J., Chen, H.-Y., Peng, S.-J., Meng, J.-L., Wang, Y., Zhou, Y., Qian, X.-P., Sun, X.-Y., Pang, X.-W., Zhang, Y., Zhang, J. USP7-TRIM27 axis negatively modulates antiviral type I IFN signaling.

Prostaglandin E2 Inhibits Group 2 Innate Lymphoid Cell Activation and Allergic Airway Inflammation Through E-Prostanoid 4-Cyclic Adenosine Monophosphate Signaling.

Evidence is accumulating that group 2 innate lymphoid cells (ILC2) play an important role in allergic airway inflammation by producing a large amount of type 2 cytokines. But it remains poorly understood how its activities are properly controlled in vivo. Here, we demonstrated that prostaglandin E2 (PGE2) had a profound inhibitory effect on IL-33-induced ILC2 expansion and IL-5 and IL-13 production in vitro. This effect was mimicked by PGE1-alcohol but attenuated by ONO-AE3-208, indicating a selective action through the E-prostanoid 4 (EP4) receptor. In the IL-33-induced asthma model, coadministration of PGE2 or PGE1-alcohol resulted in diminished IL-5 and IL-13 production, reduced eosinophilia and alleviated lung pathology. In contrast, EP4-deficient mice displayed an exacerbated inflammatory response in another ILC2-mediated asthma model induced by Alternaria extract. Mechanistic studies demonstrated that the PGE2-mediated inhibition of ILC2 was dependent on cyclic adenosine monophosphate (cAMP) production. Further downstream, PGE2-EP4-cAMP signaling led to suppression of GATA3 and ST2 expression, which is known to be critical for ILC2 activation. These findings reveal a novel function of PGE2 as a negative regulator of ILC2 activation and highlight an endogenous counter-regulatory mechanism for the control of innate allergic inflammatory responses.

Newly Generated CD4+ T Cells Acquire Metabolic Quiescence after Thymic Egress.

Mature naive T cells circulate through the secondary lymphoid organs in an actively enforced quiescent state. Impaired cell survival and cell functions could be found when T cells have defects in quiescence. One of the key features of T cell quiescence is low basal metabolic activity. It remains unclear at which developmental stage T cells acquire this metabolic quiescence. We compared mitochondria among CD4 single-positive (SP) T cells in the thymus, CD4+ recent thymic emigrants (RTEs), and mature naive T cells in the periphery. The results demonstrate that RTEs and naive T cells had reduced mitochondrial content and mitochondrial reactive oxygen species when compared with SP thymocytes. This downregulation of mitochondria requires T cell egress from the thymus and occurs early after young T cells enter the circulation. Autophagic clearance of mitochondria, but not mitochondria biogenesis or fission/fusion, contributes to mitochondrial downregulation in RTEs. The enhanced apoptosis signal-regulating kinase 1/MAPKs and reduced mechanistic target of rapamycin activities in RTEs relative to SP thymocytes may be involved in this mitochondrial reduction. These results indicate that the gain of metabolic quiescence is one of the important maturation processes during SP-RTE transition. Together with functional maturation, it promotes the survival and full responsiveness to activating stimuli in young T cells.

Thymic homing of activated CD4+ T cells induces degeneration of the thymic epithelium through excessive RANK signaling.

Activated T cells have been shown to be able to recirculate into the thymus from the periphery. The present study was aimed to elucidate the functional consequences of thymic homing of activated T cells upon developing thymocytes and thymic epithelial cells (TEC). In the presence of activated T cells, especially CD4+ T cells, T cell development was found to be inhibited in thymic organ cultures with markedly reduced cellularity. Thymic transplantation demonstrated that the inhibitory effect was most likely due to a defective microenvironment. As the major component of the thymic stroma, the TEC compartment was severely disturbed after prolonged exposure to the activated T cells. In addition to reduced cell proliferation, TEC differentiation was heavily skewed to the mTEC lineage. Furthermore, we demonstrated that RANKL highly expressed by activated CD4+ T cells was primarily responsible for the detrimental effects. Presumably, excessive RANK signaling drove overproduction of mTECs and possibly exhaustion of epithelial progenitors, thereby facilitating the deterioration of the epithelial structures. These findings not only reveal a novel activity of activated T cells re-entering the thymus, but also provide a new perspective for understanding the mechanism underlying thymic involution.