E protein binding at the Tcra enhancer promotes Tcra repertoire diversity.

V(D)J recombination of antigen receptor loci is a highly developmentally regulated process. During T lymphocyte development, recombination of the Tcra gene occurs in CD4+CD8+ double positive (DP) thymocytes and requires the Tcra enhancer (Eα). E proteins are known regulators of DP thymocyte development and have three identified binding sites in Eα. To understand the contribution of E proteins to Eα function, mutants lacking one or two of the respective binding sites were generated. The double-binding site mutant displayed a partial block at the positive selection stage of αß T cell development. Further investigation revealed loss of germline transcription within the Tcra locus at the Jα array, along with dysregulated primary and impaired secondary Vα-Jα rearrangement. Eα E protein binding increases Tcra locus accessibility and regulates TCRα recombination, thus directly promoting Tcra repertoire diversity.

Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions.

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors.

Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-ß selection thymocytes.

Production of a functional peripheral T cell compartment typically involves massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment of double-negative (DN) 2 cells and after successful rearrangement and selection for functional TCRß chains in DN3 thymocytes, which promotes the transition of DN4 cells to the DP stage. The signals driving the expansion of DN2 thymocytes are well studied. However, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-ß-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor regulating the survival of proliferating post-ß-selection thymocytes and demonstrates a key role for the cGAS/STING pathway in driving apoptosis of developing T cells.

Synergistic action of organophosphates and COVID-19 on inflammation, oxidative stress, and renin-angiotensin system can amplify the risk of cardiovascular maladies.

Organophosphates (OPs) are ubiquitous environmental contaminants, widely used as pesticides in agricultural fields. In addition, they serve as flame-retardants, plasticizers, antifoaming or antiwear agents in lacquers, hydraulic fluids, and floor polishing agents. Therefore, world-wide and massive application of these compounds have increased the risk of unintentional exposure to non-targets including the human beings. OPs are neurotoxic agents as they inhibit the activity of acetylcholinesterase at synaptic cleft. Moreover, they can fuel cardiovascular issues in the form of myocardities, cardiac oedema, arrhythmia, systolic malfunction, infarction, and altered electrophysiology. Such pathological outcomes might increase the severity of cardiovascular diseases which are the leading cause of mortality in the developing world. Coronavirus disease-19 (COVID-19) is the ongoing global health emergency caused by SARS-CoV-2 infection. Similar to OPs, SARS-CoV-2 disrupts cytokine homeostasis, redox-balance, and angiotensin-II/AT1R axis to promote cardiovascular injuries. Therefore, during the current pandemic milieu, unintentional exposure to OPs through several environmental sources could escalate cardiac maladies in patients with COVID-19.

Effectiveness of neurofeedback training, behaviour management including attention enhancement training and medication in children with attention-deficit/hyperactivity disorder - A comparative follow up study.

BACKGROUND: Attention Deficit/ Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental psychiatric disorders of childhood. Treatment of ADHD includes medications and Behavioural interventions. Neurofeedback, a type of biofeedback, has been found to be useful in ADHD. It helps patients to control their brain waves consciously. However, it is not yet conclusive if it is efficacious in comparison to behavioural management training and medication. AIM: To compare the efficacy of neurofeedback training, behaviour management including attention enhancement training and medication in children with ADHD. METHOD: Ninety children between 6 and 12 years with ADHD were taken and randomly divided into 3 treatment groups equally- neurofeedback, behaviour management and medication (methylphenidate). Conners 3-P Short Scale was applied for baseline assessment. The respective interventions were given and follow up was done at the end of 3 months by using Conners 3-P Short scale to assess the improvement in the symptoms. There were 6 dropouts, the final sample size was 84. RESULTS: The medication group showed the greatest reduction of symptoms in inattention, hyperactivity, executive functioning domain (core symptoms of ADHD). No statistically significant difference was observed between Neurofeedback and Behaviour Management in these domains. Learning problems improved in all three groups, neurofeedback being the most effective followed by medication. Both Neurofeedback and Medication groups showed similar effect which was higher than the Behavioural Management group in Peer Relation. CONCLUSION: Improvement in core ADHD symptoms have been observed with all 3 interventions with medication showing the greatest improvement Neurofeedback has been superior for learning problems. Thus, Neurofeedback can be an independent or combined intervention tool for children with ADHD in outpatient department of Psychiatry.

In silico study reveals binding potential of rotenone at multiple sites of pulmonary surfactant proteins: A matter of concern.

Rotenone is a broad-spectrum pesticide employed in various agricultural practices all over the world. Human beings are exposed to this chemical through oral, nasal, and dermal routes. Inhalation of rotenone exposes bio-molecular components of lungs to this chemical. Biophysical activity of lungs is precisely regulated by pulmonary surfactant to facilitate gaseous exchange. Surfactant proteins (SPs) are the fundamental components of pulmonary surfactant. SPs like SP-A and SP-D have antimicrobial activities providing a crucial first line of defense against infections in lungs whereas SP-B and SP-C are mainly involved in respiratory cycle and reduction of surface tension at air-water interface. In this study, molecular docking analysis using AutoDock Vina has been conducted to investigate binding potential of rotenone with the four SPs. Results indicate that, rotenone can bind with carbohydrate recognition domain (CRD) of SP-A, N-, and C- terminal peptide of SP-B, SP-C, and CRD of SP-D at multiples sites via several interaction mediators such as H bonds, C-H bonds, alkyl bonds, pi-pi stacked, Van der Waals interaction, and other. Such interactions of rotenone with SPs can disrupt biophysical and anti-microbial functions of SPs in lungs that may invite respiratory ailments and pathogenic infections.

Understanding the cross-talk between mediators of infertility and COVID-19.

COVID-19 is the ongoing health emergency affecting individuals of all ages around the globe. Initially, the infection was reported to affect pulmonary structures. However, recent studies have delineated the impacts of COVID-19 on the reproductive system of both men and women. Hence, the present review aims to shed light on the distribution of SARS-CoV-2 entry factors in various reproductive organs. In addition, impacts of COVID-19 mediators like disrupted renin angiotensin system, oxidative stress, cytokine storm, fever, and the mental stress on reproductive physiology have also been discussed. For the present study, various keywords were used to search literature on PubMed, ScienceDirect, and Google Scholar databases. Articles were screened for relevancy and were studied in detail for qualitative synthesis of the review. Through our literature review, we found a multitude of effects of COVID-19 mediators on reproductive systems. Studies reported expression of receptors like ACE-2, TMPRSS2, and CD147 in the testes, epididymis, prostrate, seminal vesicles, and ovarian follicles. These proteins are known to serve as major SARS-CoV-2 entry factors. The expression of lysosomal cathepsins (CTSB/CTSL) and/ neuropilin-1 (NRP-1) are also evident in the testes, epididymis, seminal vesicles, fallopian tube, cervix, and endometrium. The binding of viral spike protein with ACE-2 was found to alter the renin-angiotensin cascade, which could invite additional infertility problems. Furthermore, COVID-19 mediated cytokine storm, oxidative stress, and elevated body temperature could be detrimental to gametogenesis, steroidogenesis, and reproductive cycles in patients. Finally, social isolation, confinement, and job insecurities have fueled mental stress and frustration that might promote glucocorticoid-mediated subnormal sperm quality in men and higher risk of miscarriage in women. Hence, the influence of COVID-19 on the alteration of reproductive health and fertility is quite apparent.

Immunotoxic role of organophosphates: An unseen risk escalating SARS-CoV-2 pathogenicity.

Consistent gathering of immunotoxic substances on earth is a serious global issue affecting people under pathogenic stress. Organophosphates are among such hazardous compounds that are ubiquitous in nature. They fuel oxidative stress to impair antiviral immune response in living entities. Aside, organophosphates promote cytokine burst and pyroptosis in broncho-alveolar chambers leading to severe respiratory ailments. At present, we witness COVID-19 outbreak caused by SARS-CoV-2. Infection triggers cytokine storm coupled with inflammatory manifestations and pulmonary disorders in patients. Since organophosphate-exposure promotes necroinflammation and respiratory troubles hence during current pandemic situation, additional exposure to such chemicals can exacerbate inflammatory outcome and pulmonary maladies in patients, or pre-exposure to organophosphates might turn-out to be a risk factor for compromised immunity. Fortunately, antioxidants alleviate organophosphate-induced immunosuppression and hence under co-exposure circumstances, dietary intake of antioxidants would be beneficial to boost immunity against SARS-CoV-2 infection.

A mosaic analysis system with Cre or Tomato expression in the mouse.

Somatic mutations are major genetic contributors to cancers and many other age-related diseases. Many disease-causing somatic mutations can initiate clonal growth prior to the appearance of any disease symptoms, yet experimental models that can be used to examine clonal abnormalities are limited. We describe a mosaic analysis system with Cre or Tomato (MASCOT) for tracking mutant cells and demonstrate its utility for modeling clonal hematopoiesis. MASCOT can be induced to constitutively express either Cre-GFP or Tomato for lineage tracing of a mutant and a reference group of cells simultaneously. We conducted mosaic analysis to assess functions of the Id3 and/or Tet2 gene in hematopoietic cell development and clonal hematopoiesis. Using Tomato-positive cells as a reference population, we demonstrated the high sensitivity of this system for detecting cell-intrinsic phenotypes during short-term or long-term tracking of hematopoietic cells. Long-term tracking of Tet2 mutant or Tet2/Id3 double-mutant cells in our MASCOT model revealed a dynamic shift from myeloid expansion to lymphoid expansion and subsequent development of lymphoma. This work demonstrates the utility of the MASCOT method in mosaic analysis of single or combined mutations, making the system suitable for modeling somatic mutations identified in humans.

Potential risk of organophosphate exposure in male reproductive system of a non-target insect model Drosophila melanogaster.

Based on several adverse reports of pesticides on reproductive efficiency of various organisms, studies on "reproductive toxicity" have gained importance. Fecundity, reflecting reproductive success of any organism, is governed by several factors from female and male reproductive systems. This present study explored morphological and biochemical alterations in the male reproductive system of a non-target model organism, Drosophila melanogaster following chronic sub-lethal exposure (1st instar larvae differentially exposed to 1-6 µg/mL until adulthood) to the organophosphate (OP) pesticide, acephate (chronic LC50 8.71 µg/mL). This study demonstrates altered testis structure, decreased germ cell viability and gross body weight, increased activities of oxidative stress marker lipid peroxidase (LPO), and the endogenous antioxidant enzyme catalase (CAT)in addition with altered expression of reproductive marker proteins like vitellogenin and mitoferrin in acephate-exposed flies when compared to control counterparts. Altered reproductive behavior, indicated by a significant decline in the number of mating pairs, validates the adverse effect of chronic acephate exposure on male reproduction in the non-target insect model D. melanogaster.

E-protein-regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex.

Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR-CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4-CXCL12 engagements release preselection thymocytes from the thymic cortex. We further document that CXCR4 expression must be extinguished by TCR-mediated positive selection signals to allow migration of TCR-signaled thymocytes out of the thymic cortex into the medulla. Thus, E-protein transcription factors regulate the ordered expression pattern of chemokine receptors on developing thymocytes, and the interaction of the chemokine receptor CXCR4 with its ligand adheres TCR-unsignaled preselection thymocytes to the thymic cortex.

Chronic exposure to acephate triggers ROS-mediated injuries at organismal and sub-organismal levels of Drosophila melanogaster.

The present study demonstrates ROS-mediated organismal and sub-organismal injuries in Drosophila melanogaster following chronic acephate exposure. Larvae and adults of Drosophila were reared on food supplemented with sub-lethal concentrations (1-6 µg mL-1) of acephate (LC50 8.71 µg mL-1). The longevity of the treated adults was reduced to half at 6 µg mL-1 exposure along with declined neuromuscular coordination and physical activities. Apparent developmental defects in the compound eyes were confirmed through the detection of apoptotic lesions in larval eye imaginal discs. The larval gut manifested tissue damage at various sites. Neural and fat cell viability was reduced by ∼1.89- and ∼3.38-fold at 6 µg mL-1 acephate treatment, respectively. A significant reduction in hemocyte viability confirmed the immunotoxic potential of acephate. Nearly 1-3-fold enhancement in the expression of OS markers (MDA, protein carbonyl contents, SOD, catalase and HSP70) in the treated larvae served as evidence of ROS production. The post-treatment increase in CYP450 and GST activities reflects the 'switch-on' states of the phase-I and phase-II detoxification mechanism. The genotoxic potential of acephate was confirmed through alkaline single cell gel electrophoresis. Thus, the findings of the present study validate the fact that besides traditional cholinesterase inhibition, chronic sub-lethal exposure to acephate potentially induces ROS-mediated toxic responses in Drosophila.

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells.

A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt's lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

Interplay of ROS and behavioral pattern in fluoride exposed Drosophila melanogaster.

Reactive oxygen species (ROS) is known to be associated with the process of aging and other health hazards. Organisms are compelled to compromise with body homeostasis when exposed to toxic substances. In the present study sodium fluoride (NaF) exposure (10-100 µgmL-1) to Drosophila melanogaster in the parental (P) generation leads to increase in adult mortality and alteration in male-female ratio in the P and F1 (1st Filial) generation. Post-treatment alterations in selected behavioral traits (crawling, embedding and climbing) were observed in larvae and adults. Altered behavioral pattern was found to be associated with reduced mitochondrial activity and decreased number of viable brain cells in treated individuals. Interestingly, higher cholinesterase activities in treated males in comparison to females demonstrate a definite sex bias in NaF-induced response. Hyper-activation of antioxidant enzyme like catalase and reduced superoxide dismutase (SOD) and glutathione-s-transferase (GST) activity indicate a shift in the oxidative status after fluoride exposure. Additionally, increase in lipid peroxidation suggests enhancement in ROS which is further validated through increment in protein carbonyl content. Hence, the observations of the present study propose behavioral alterations resulting from increased ROS after chronic exposure to sub-lethal concentrations of NaF in D. melanogaster.

Flubendiamide affects visual and locomotory activities of Drosophila melanogaster for three successive generations (P, F1 and F2).

Flubendiamide is widely used in agricultural fields to exterminate a broad spectrum of pests (lepidopteran insects) by disrupting their muscle function. The main objective of this study was to find the effects of flubendiamide on a non-target organism, Drosophila melanogaster (dipteran insect). In the present study, different sub-lethal concentrations of Flubendiamide caused a significant (P < 0.05) decrease in acetylcholinesterase activity and increase in cytochrome P450 activity in adult D. melanogaster. Phototaxis and climbing behaviours were found to significantly (P < 0.05) alter in exposed flies. The observed alteration in phototaxis and climbing behaviours were not restricted to P generation, but were found to be transmitted to subsequent generations (F1 and F2 generation) that had never been directly exposed to the test chemical during their life time. It is only their predecessors (P generation) who have been affronted with different concentrations of Flubendiamide. Humans and Drosophilids share almost 60% genomic similarity and 75% disease gene resemblance. Moreover, most of the circuits governing the behaviours studied involve the inhibition and excitation of neurotransmitters, which are conserved in humans and flies. Thus, the present findings suggest that chronic flubendiamide exposure might induce alteration in neurotransmission leading to discrepancy in the behavioural responses (vision and flight) in other beneficial insects and insect-dependent organisms.

Id Proteins Suppress E2A-Driven Invariant Natural Killer T Cell Development prior to TCR Selection.

A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αß T cells and suppress the expansion of innate-like αß T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional αß T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional αß T cells.

Trans-generational transmission of altered phenotype resulting from flubendiamide-induced changes in apoptosis in larval imaginal discs of Drosophila melanogaster.

The eye and wing morphology of Drosophila melanogaster maintain unique, stable pattern of genesis from larval eye and wing imaginal discs. Increased apoptosis in cells of eye and wing discs was found to be associated with flubendiamide (fluoride containing insecticide) exposure (at the range 0.25-10µg/mL) in D. melanogaster larvae. The chemical fed larvae on attaining adulthood revealed alterations in morphology and symmetry of their compound eyes and wings through scanning electron microscopy. Nearly 40% and 30% of flies (P generation) demonstrated alterations in eyes and wings respectively. Transmission electron microscopic study (at the range 1-20µg/mL) also established variation in the rhabdomere and pigment cell orientation as well as in the shape of the ommatidium. Subsequent SEM study with F1 and F2 generation flies also revealed structural variation in eye and wing. Decrease in percentage of altered eye and wing phenotype was noted in subsequent generations (P> F1>F2). Thus, the diamide insecticide, flubendiamide, expected to be environmentally safe at sub-lethal concentrations was found to increase apoptosis in larvae and thereby cause morphological alteration in the adult D. melanogaster. This study further demonstrated trans-generational transmission of altered phenotype in three subsequent generations of a non-target insect model, D. melanogaster.

Monitoring the effects of a lepidopteran insecticide, Flubendiamide, on the biology of a non-target dipteran insect, Drosophila melanogaster.

Various organisms are adversely affected when subjected to chronic fluoride exposure. This highly electronegative ion present in several insecticide formulations is found to be lethal to target pests. In the present study, Drosophila melanogaster is treated with sub-lethal concentrations of a diamide insecticide formulation, Flubendiamide. Chronic exposure to the diamide (0.5-100 µg/mL) was found to be responsible for increase in fluoride ion concentration in larval as well as adult body fluid. Interestingly, 100 µg/mL Flubendiamide exposure resulted in 107 and 298% increase in fluoride ion concentration whereas only 23 and 52% of Flubendiamide concentration increase in larval and adult body fluid, respectively. Further, in this study, selected life cycle parameters like larval duration, pupal duration and emergence time showed minimal changes, whereas percentage of emergence and fecundity revealed significant treatment-associated variation. It can be noted that nearly 79% reduction in fecundity was observed with 100 µg/mL Flubendiamide exposure. The variations in these parameters indicate probable involvement of fluoride ion in detectable alterations in the biology of the non-target model insect, D. melanogaster. Furthermore, the outcomes of life cycle study suggest change in resource allocation pattern in the treated flies. The altered resource allocation might have been sufficient to resist changes in selective life cycle parameters, but it could not defend the changes in fecundity. The significant alterations indicate a definite trade-off pattern, where the treated individuals happen to compromise. Thus, survival is apparently taking an upper hand in comparison to reproductive ability in response to Flubendiamide exposure. Graphical abstract The figure demonstrates increase in Fluoride and Flubendiamide concentrations in Drosophila melanogaster after chronic sub-lethal exposure to Flubendiamide. Treatment-induced alterations in larval and pupal duration, reduction in fecundity and alteration in male-female ratio is also observed.

Sodium fluoride adversely affects ovarian development and reproduction in Drosophila melanogaster.

The study demonstrates the effects of chronic sub-lethal exposure of sodium fluoride (NaF) on reproductive structure and function of female Drosophila melanogaster. As a part of treatment, flies were maintained in food supplemented with sub-lethal concentrations of NaF (10-100 µg/mL). Fecundity, ovarian morphology, presence and profusion of viable cells from ovary and fat body were taken into consideration for evaluating changes in reproductive homeostasis. Wing length (a factor demonstrating body size and reproductive fitness) was also monitored after NaF exposure. Significant reduction in fecundity, alteration in ovarian morphology along with an increase in apoptosis was observed in treated females. Simultaneous decline in viable cell number and larval weight validates the result of MTT assay. Furthermore, altered ovarian Glucose-6-phosphate dehydrogenase and catalase activities together with increased rate of lipid peroxidation after 20 and 40 µg/mL NaF exposure confirmed the changes in reproduction related metabolism. Enhanced lipid peroxidation known for ROS generation might have induced genotoxicity which is confirmed through Comet assay. The enzyme activities were not dose dependent, rather manifested a bimodal response, which suggests a well-knit interaction among the players inducing stress and the ones that help establish physiological homeostasis.

Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors.

Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development in Id2/Id3 double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared between Id2/Id3 double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.