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Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8+ T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103+CD8+ T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103+CD8+ T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103+CD8+ T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8+ T cell response to acute viral infection. There is a reduction in resident CD103+CD8+ T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8+ T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103+CD8+ T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103+CD8+ T cell response to promote protective immunity.

The metabolic stress present in tumors microenvironment (TME) attenuates T cells anti-tumor capacity, whereas the immune function of T cells is intrinsically controlled by their mitochondrial plasticity including mitochondrial dynamics, metabolism and biogenesis. Previous studies have reported that the complement C1q binding protein (C1QBP), a mitochondrial protein, is responsible for maintenance of the mitochondrial integrity and fitness in dendritic cells and tumor cells. However, its role in T cells, especially in T cells mediated anti-tumor immunity, remains unclear. Here we show that C1QBP is required to maintain T cell anti-tumor immunity by regulating mitochondrial biogenesis, dynamics and metabolic fitness even when only one allele of C1qbp is deleted, without affecting T cells development and homeostasis. Further analysis of C1QBP in the chimeric antigen receptor (CAR) T cell therapy against B16 melanoma model confirmed the cell intrinsic role of C1QBP in regulating T cells antitumor function. Mechanistically, we found C1QBP regulated mitochondrial plasticity and metabolic fitness through mitochondrial biogenesis via the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) signaling pathway, as well as mitochondrial morphology via the phosphorylation of mitochondrial dynamics protein dynamin-related protein 1 (Drp1). In summary, our study provides a novel mitochondrial target to reprogram the immune metabolism of T cells and improve their immunotherapeutic potential against tumors.

Recent discovery of the ribosomal protein (RP) RPL11 interacting with and inhibiting the E3 ubiquitin ligase function of MDM2 established the RP-MDM2-p53 signaling pathway, which is linked to biological events, including ribosomal biogenesis, nutrient availability, and metabolic homeostasis. Mutations in RPs lead to a diverse array of phenotypes known as ribosomopathies in which the role of p53 is implicated. Here, we generated conditional RPL11-deletion mice to investigate in vivo effects of impaired RP expression and its functional connection with p53. While deletion of one Rpl11 allele in germ cells results in embryonic lethality, deletion of one Rpl11 allele in adult mice does not affect viability but leads to acute anemia. Mechanistically, we found RPL11 haploinsufficiency activates p53 in hematopoietic tissues and impedes erythroid precursor differentiation, resulting in insufficient red blood cell development. We demonstrated that reducing p53 dosage by deleting one p53 allele rescues RPL11 haploinsufficiency-induced inhibition of erythropoietic precursor differentiation and restores normal red blood cell levels in mice. Furthermore, blocking the RP-MDM2-p53 pathway by introducing an RP-binding mutation in MDM2 prevents RPL11 haploinsufficiency-caused p53 activation and rescues the anemia in mice. Together, these findings demonstrate that the RP-MDM2-p53 pathway is a critical checkpoint for RP homeostasis and that p53-dependent cell cycle arrest of erythroid precursors is the molecular basis for the anemia phenotype commonly associated with RP deficiency.

The inflammasome initiates innate defense and inflammatory response by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It is comprised of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC (apoptotic speck-containing protein with a CARD). Consistent with their pro-inflammatory function, caspase-1, ASC and NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) by enhancing IL-1β and IL-18 secretion in myeloid cells3–6. Here we reveal an unexpected function of a DNA-binding inflammasome receptor, AIM2 (Absent in Melanoma 2)7–10, in T regulatory cells (Tregs) to restrain two models of autoimmunity (experimental autoimmune encephalomyelitis and T cell-mediated colitis) by studying whole-body and Treg-specific Aim2–/– mice. AIM2 is highly expressed by human and mouse Tregs, with its expression induced by TGF-β and its promoter occupied by transcription factors associated with Tregs, including Runx1, Ets1, Bcl11b and CREB. RNA-seq, biochemical and metabolic analyses revealed that AIM2 attenuates Akt-phosphorylation, mTOR, c-Myc and glycolysis, but promotes lipid oxidative phosphorylation in Tregs. Mechanistically, AIM2 interacts with the RACK1/PP2A-phosphatase complex to restrain Akt-phosphorylation. Lineage tracing demonstrates that AIM2 promotes the stability of Tregs during inflammation. While AIM2 is generally accepted as an inflammasome effector in myeloid cells, this report reveals a T cell-intrinsic role of AIM2 in restraining autoimmunity by diminishing Akt-mTOR signaling and altering immune-metabolism to enhance Treg stability.

Summary Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.

Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8(+) T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103(+)CD8(+) T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ–SKI–Smad4 pathway that critically and specifically directs resident CD103(+)CD8(+) T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103(+)CD8(+) T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8(+) T cell response to acute viral infection. There is a reduction in resident CD103(+)CD8(+) T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8(+) T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103(+)CD8(+) T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103(+)CD8(+) T cell response to promote protective immunity.

Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most common developmental defects in humans. Despite of several known CAKUT-related loci (HNF1B, PAX2, EYA1, etc.), the genetic etiology of CAKUT remains to be elucidated for most patients. In this study, we report that disruption of the Holliday Junction resolvase gene Gen1 leads to renal agenesis, duplex kidney, hydronephrosis, and vesicoureteral reflux (VUR) in mice. GEN1 interacts with SIX1 and enhances the transcriptional activity of SIX1/EYA1, a key regulatory complex of the GDNF morphogen. Gen1 mutation impairs Grem1 and Gdnf expression, resulting in excessive ureteric bud formation and defective ureteric bud branching during early kidney development. These results revealed an unidentified role of GEN1 in kidney development and suggested its contribution to CAKUT.

As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.

Summary Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production. The Th2 cell bias of Rasa3-deficient T cells was due to aberrantly elevated transcription factor IRF4 expression. RASA3 promoted proteasome-mediated IRF4 protein degradation by facilitating interaction of IRF4 with E3-ubiquitin ligase Cbl-b. Therefore, a RASA3-IRF4-Cbl-b pathway specifically directs pTh17 cell generation by balancing reciprocal Th17-Th2 cell programs. These findings indicate that a distinct molecular program directs pTh17 cell generation and reveals targets for treating pTh17 cell-related pathology and diseases.

This research aims at combined and relative effect levels on anxiety of: (1) perceived risk, knowledge, optimism, pessimism, and social trust; and (2) four sub-variables of social trust among inhabitants concerning living on heavy metal contaminated soil. On the basis of survey data from 499 Chinese respondents, results suggest that perceived risk, pessimism, optimism, and social trust have individual, significant, and direct effects on anxiety, while knowledge does not. Knowledge has significant, combined, and interactive effects on anxiety together with social trust and pessimism, respectively, but does not with perceived risk and optimism. Social trust, perceived risk, pessimism, knowledge, and optimism have significantly combined effects on anxiety; the five variables as a whole have stronger predictive values than each one individually. Anxiety is influenced firstly by social trust and secondly by perceived risk, pessimism, knowledge, and optimism. Each of four sub-variables of social trust has an individual, significant, and negative effect on anxiety. When introducing four sub-variables into one model, trust in social organizations and in the government have significantly combined effects on anxiety, while trust in experts and in friends and relatives do not; anxiety is influenced firstly by trust in social organization, and secondly by trust in the government.

On activation, naive T cells grow in size and enter cell cycle to mount immune response. How the fundamental processes of T-cell growth and cell cycle entry are regulated is poorly understood. Here we report that DCAF1 (Ddb1–cullin4-associated-factor 1) is essential for these processes. The deletion of DCAF1 in T cells impairs their peripheral homeostasis. DCAF1 is upregulated on T-cell receptor activation and critical for activation-induced T-cell growth, cell cycle entry and proliferation. In addition, DCAF1 is required for T-cell expansion and function during anti-viral and autoimmune responses in vivo. DCAF1 deletion leads to a drastic stabilization of p53 protein, which can be attributed to a requirement of DCAF1 for MDM2-mediated p53 poly-ubiquitination. Importantly, p53 deletion rescues the cell cycle entry defect but not the growth defect of DCAF1-deficient cells. Therefore, DCAF1 is vital for T-cell function through p53-dependent and -independent mechanisms., DCAF1 (VprBP), an HIV target protein, is a component of an ubiquitin ligase complex involved in developmental processes in plants and animals. Here, DCAF1 is shown to be vital for activation-induced T cell growth and proliferation, partly by being required for p53's ubiquitination and degradation.

Dihydroartemisinin (DHA) is an important derivative of the herb medicine Artemisia annua L., used in ancient China. DHA is currently used worldwide to treat malaria by killing malaria-causing parasites. In addition to this prominent effect, DHA is thought to regulate cellular functions, such as angiogenesis, tumor cell growth, and immunity. Nonetheless, how DHA affects T cell function remains poorly understood. We found that DHA potently suppressed Th cell differentiation in vitro. Unexpectedly, however, DHA greatly promoted regulatory T cell (Treg) generation in a manner dependent on the TGF-βR:Smad signal. In addition, DHA treatment effectively reduced onset of experimental autoimmune encephalomyelitis (EAE) and ameliorated ongoing EAE in mice. Administration of DHA significantly decreased Th but increased Tregs in EAE-inflicted mice, without apparent global immune suppression. Moreover, DHA modulated the mammalian target of rapamycin (mTOR) pathway, because mTOR signal was attenuated in T cells upon DHA treatment. Importantly, enhanced Akt activity neutralized DHA-mediated effects on T cells in an mTOR-dependent fashion. This study therefore reveals a novel immune regulatory function of DHA in reciprocally regulating Th and Treg cell generation through the modulating mTOR pathway. It addresses how DHA regulates immune function and suggests a new type of drug for treating diseases in which mTOR activity is to be tempered.

The Id3 gene has been shown to play important roles in the development and function of broad tissue types including B and T cells. Id3 deficient mice develop autoimmune disease similar to human Sjogren's syndrome. Both B and T lymphocytes have been implicated to contribute to the disease phenotype in this disease model. In order to gain a better understanding of individual cell types in this disease model, we generated an Id3 conditional allele. An LckCre transgene was used to induce Id3 deletion in developing T cells. We showed that the Id3 gene was efficiently disrupted in early thymocyte development prior to T cell receptor (TCR)-mediated positive selection. Consequently, thymocyte maturation was impaired in the conditional knockout mice. These mice developed exocrinopathy starting at two months of age and subsequently exhibited high incidence of lymphocyte infiltration to salivary glands between eight and 12 months of age. This progressive feature of disease development is very similar to those observed in Id3 germline knockout mice. This study establishes a new model for investigating the relationship between T cell development and autoimmune disease. Our observation provides an experimental case that autoimmune disease may be induced by acquired mutation in developing T cells.