Experiential avoidance as a mediator of risk factors for higher order internalizing psychopathology in the perinatal period.

OBJECTIVES: Perinatal psychopathology can be damaging. This study examined the strength of the associations between risk factors and all perinatal mood and anxiety disorder symptoms while assessing the mediating effect of experiential avoidance. METHOD: Participants (N = 246) completed assessments during pregnancy (28-32 weeks) and the postpartum (6-8 weeks). Structural equation modeling (SEM) was used to examine associations between risk factors and latent factors: distress (composed of depression, generalized anxiety, irritability, and panic symptoms); fear (social anxiety, agoraphobia, specific phobia, and obsessive-compulsive); and bipolar (mania and obsessive-compulsive). RESULTS: During pregnancy, past psychiatric history, anxiety sensitivity, maladaptive coping, and age were significant risk factors. In the postpartum, negative maternal attitudes and past psychiatric history were only risk factors for symptoms that composed distress. Experiential avoidance mediated the relation between maladaptive coping and symptoms that composed fear. CONCLUSION: It is important to assess for psychological risk factors starting in pregnancy. This study identified critical risk factors that are associated with the underlying commonality among perinatal mood and anxiety symptoms. Some of the risk factors as well as the mediator are malleable (negative maternal attitudes, experiential avoidance), creating new possibilities for prevention and treatment of perinatal mood and anxiety disorder symptoms.

Obsessive-compulsive and related disorder symptoms in the perinatal period: prevalence and associations with postpartum functioning.

Obsessive-compulsive disorder (OCD) symptoms are more likely to develop or be exacerbated during pregnancy and the postpartum period, which can cause significant distress and impairment. However, the disorders grouped with OCD in the DSM-5, obsessive-compulsive and related disorders (OCRD; e.g., hoarding disorder (HD), body dysmorphic disorder (BDD), trichotillomania (TTM), excoriation disorder (ED)), have rarely been examined in the perinatal period. This study aimed to explore (1) the prevalence of all clinically significant OCRD symptoms in pregnancy and the postpartum period and (2) the correlations between OCRD psychopathology and postpartum functioning. Participants were recruited during their second trimester of pregnancy from a Midwestern medical center. Participants completed an online questionnaire and a semi-structured clinical interview during pregnancy (28-32 weeks' gestation, N = 276) and the postpartum period (6-8 weeks, N = 221). BDD and OCD symptoms were the most prevalent. In pregnancy, 14.9% (N = 41) of participants endorsed clinically significant BDD symptoms and 6.2% (N = 17) endorsed clinically significant OCD symptoms. In the postpartum period, 11.8% (N = 26) endorsed clinically significant BDD symptoms and 14% (N = 31) endorsed clinically significant OCD symptoms. Poorer postpartum functioning was associated with elevated OCRD symptoms in pregnancy and postpartum. OCRD symptoms occur during pregnancy and the postpartum period at rates similar or higher than other life periods. Elevated OCRD symptoms are associated with poorer postpartum functioning across domains. Future research should explore how all OCRD symptoms may affect functioning in the perinatal period, not only OCD symptoms.

Treating posttraumatic stress disorder at home in a single week using 1-week virtual massed cognitive processing therapy.

Posttraumatic stress disorder (PTSD) treatments are increasingly delivered in massed formats and have shown comparable results to standard, weekly treatment. To date, massed cognitive processing therapy (CPT), delivered daily, has been delivered primarily in combination with adjunctive services and among veteran populations, but it has not been rigorously evaluated as a standalone intervention. The present study evaluated 1-week massed CPT delivered virtually (i.e., via telehealth) to a community sample of trauma-exposed individuals (N = 24). Using a single-arm open-label design, participants received CPT twice per day for 5 days. The results indicated that most participants completed treatment (n = 23, 95.8%), and no adverse events were reported. Participants exhibited large reductions in clinician-rated, d = 2.01, and self-reported PTSD symptoms, d = 2.55, as well as self-reported depressive symptoms, d = 1.46. On average, participants reported a 5-point PTSD symptom reduction and 1-point reduction in depressive symptoms for each treatment day. Reductions in PTSD and depressive symptoms were maintained at 3-month follow-up. Overall, 1-week massed CPT delivered virtually was shown to be feasible and to result in rapid symptom reductions that were sustained over time. Virtual massed CPT has the potential to increase access to effective treatments and help trauma survivors restore aspects of their lives in short amounts of time.

Resilience of T cell-intrinsic dysfunction in transplantation tolerance.

Following antigen stimulation, naïve T cells differentiate into memory cells that mediate antigen clearance more efficiently upon repeat encounter. Donor-specific tolerance can be achieved in a subset of transplant recipients, but some of these grafts are rejected after years of stability, often following infections. Whether T cell memory can develop from a tolerant state and whether these formerly tolerant patients develop antidonor memory is not known. Using a mouse model of cardiac transplantation in which donor-specific tolerance is induced with costimulation blockade (CoB) plus donor-specific transfusion (DST), we have previously shown that systemic infection with Listeria monocytogenes (Lm) months after transplantation can erode or transiently abrogate established tolerance. In this study, we tracked donor-reactive T cells to investigate whether memory can be induced when alloreactive T cells are activated in the setting of tolerance. We show alloreactive T cells persist after induction of cardiac transplantation tolerance, but fail to acquire a memory phenotype despite becoming antigen experienced. Instead, donor-reactive T cells develop T cell-intrinsic dysfunction evidenced when removed from the tolerant environment. Notably, Lm infection after tolerance did not rescue alloreactive T cell memory differentiation or functionality. CoB and antigen persistence were sufficient together but not separately to achieve alloreactive T cell dysfunction, and conventional immunosuppression could substitute for CoB. Antigen persistence was required, as early but not late surgical allograft removal precluded the acquisition of T cell dysfunction. Our results demonstrate transplant tolerance-associated T cell-intrinsic dysfunction that is resistant to memory development even after Lm-mediated disruption of tolerance.

Communal mastery and associations with depressive and PTSD symptomatology among urban trauma-exposed women.

Objective: Racial and ethnic minority women from low-resource urban communities experience disproportionately high rates of trauma exposure. Higher rates of lifetime trauma exposure are strongly associated with subsequent psychological sequela, specifically depression and posttraumatic stress disorder (PTSD). Communal mastery is the ability to cope with challenges and achieve goals by being closely interconnected with friends, family, and significant others. Yet, it is unknown if communal mastery is protective specifically against PTSD and depressive symptoms. Method: Participants (N = 131) were Black and Latina women (88.5% Black, mean monthly income: < $750) recruited from an urban outpatient obstetric-gynecological clinic at an academic medical center. Participants completed an online questionnaire that assessed trauma history, PTSD and depressive symptoms, types of individualistic coping, social support, and communal mastery. Results: Hierarchical multiple regression models demonstrated that communal mastery is uniquely associated with fewer PTSD symptoms (ß = -.23, p = .003). More severe trauma history, more use of passive coping skills, and poorer social support were also significantly associated with PTSD symptoms, explaining over half of the variance in PTSD symptoms. Although significantly correlated, communal mastery was not uniquely associated with fewer depressive symptoms (ß = -.13, p = .201). Conclusions: These findings suggest that connectedness as assessed through communal mastery serves as an important shield against the effects of traumatic stress for Black and Latina women. Future research would benefit by exploring interventions that aim to increase communal mastery in order to help highly trauma-exposed racial and ethnic minority women in low-resource environments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Psychological Intervention and Treatment for Posttraumatic Stress Disorder During Pregnancy: A Systematic Review and Call to Action.

Posttraumatic stress disorder (PTSD) during pregnancy is a significant global mental health concern that affects up to 1 in 5 trauma-exposed pregnant women and is associated with an increased risk of adverse maternal and infant complications and health outcomes. This systematic literature review, conducted in accordance with PRISMA guidelines, examined findings from studies of psychological interventions and treatments for prenatal PTSD to inform recommendations for future research. Relevant evidence was identified from reference reviews and electronic databases (i.e., PubMed, Google Scholar, PsychInfo, and Scopus). Included studies reported on the effect of nonpharmacological intervention or treatment of PTSD symptomatology delivered during pregnancy, with at least one postintervention follow-up collected during pregnancy to assess prenatal treatment outcomes. The systematic review was augmented with a discussion of lower-level evidence. Of the 954 articles screened, six peer-reviewed, quantitative reports met the inclusion criteria and featured three empirically based interventions, including two randomized controlled trials: Two psychoeducation interventions for PTSD and one treatment study of interpersonal psychotherapy in trauma-exposed pregnant women. Effect sizes for PTSD symptom change ranged from small to large, Cohen's d/ηp 2 = 0.16-0.78. No studies examined evidence-based PTSD treatments (e.g., exposure therapy, cognitive processing therapy). A risk of bias assessment indicated variability in study quality. This review demonstrates that research on prenatal PTSD symptoms, diagnosis, and treatment is extremely limited despite a clear link between prenatal PTSD and perinatal complications. Early evidence supports further scientific inquiry into psychoeducation, psychotherapy treatments (e.g., exposure therapy), integrated prenatal care approaches, and community-based approaches.

Depressive and Anxiety Symptoms Predict Obsessive and Compulsive Cravings among Depressed Alcoholics.

Objectives: Alcohol craving is often associated with mood symptoms and predicts alcohol use in individuals with alcohol dependence. However, little is known about the impact of mood symptoms on alcohol craving in comorbid mood disorders and alcohol dependence. This study examines the predictive value of depressive and anxiety symptoms for obsessive and compulsive aspects of alcohol craving in adults with comorbid Major Depressive Disorder (MDD) and Alcohol Dependence. Methods: Fifty-five adults (47% female; mean age of 39.35 (SD=8.80)) with DSM-IV diagnoses of comorbid MDD and alcohol dependence were prospectively assessed over a six-month period. They completed the Hamilton Rating Scales for Depression and Anxiety, the Alcohol Timeline Followback, the Obsessive Compulsive Drinking Scale (OCDS), the Alcohol Dependence Scale (ADS), and the Addiction Severity Index (ASI). The linear mixed model analyses for repeated measures was used to test weather depressive and anxiety symptoms predict OCDS subscale scores. Results: Depressive and anxiety symptoms were strongly associated with obsessive and compulsive subscales of the OCDS. Baseline ASI-alcohol scores were associated with both the obsessive and compulsive and with the obsessive subscale scores in the predictive model including depressive symptoms, and that including anxiety symptoms respectively. Conclusions: Results suggest that depressive and anxiety symptoms predict obsessive and compulsive aspects of alcohol craving in adults with comorbid MDD and alcohol dependence. Assessing the severity of depressive and anxiety symptoms and alcohol use in this population may identify those more likely to experience intense alcohol craving states and at increased risk of relapse.

Obsessive-compulsive symptoms, intrusive thoughts and depressive symptoms: a longitudinal study examining relation to maternal responsiveness.

BACKGROUND: The postpartum period is a vulnerable time for the development of depression. While perinatal depression has been well studied, intrusive thoughts related to the infant and classic obsessive-compulsive (OC) symptoms (e.g. chequering, ordering and cleaning) are also common in the postpartum and less well understood. OBJECTIVE: The present study investigated the associations among depressive symptoms, intrusive thoughts, and OC symptoms and their relation to the quality of the mother-infant relationship, particularly in the realm of maternal responsiveness. METHODS: Participants (N = 228) were recruited after delivery from a large Midwestern academic medical centre. At 2 and 12-week postpartum, participants completed self-report questionnaires that assessed demographics, depressive and OC symptoms, postpartum-specific intrusive thoughts and accompanying neutralising strategies, and maternal responsiveness. RESULTS: At 12-week postpartum, maternal responsiveness was significantly lower for participants that endorsed intrusive thoughts, neutralising strategies or OC symptoms of clinical significance. More severe intrusive thoughts and neutralising strategies were associated with maternal responsiveness but not predictive after accounting for depressive symptoms; depressive symptoms were associated with lower levels of maternal responsiveness across the postpartum. CONCLUSIONS: A sizable number of postpartum women experience clinically significant postpartum-specific intrusive thoughts and utilise neutralising strategies, especially in the context of postpartum depressive symptoms. Depressive symptoms have the most influence on maternal responsiveness but it is also important to target intrusive thoughts and OC symptoms in the context of postpartum depression to promote the welfare of new mothers and their offspring.

Long-Term Cognitive and Psychological Functioning in Post-Electroconvulsive Therapy Patients.

OBJECTIVE: Electroconvulsive therapy (ECT) is associated with positive outcomes for treatment-resistant mood disorders in the short term. However, there is limited research on long-term cognitive or psychological changes beyond 1 year after -ECT. This study evaluated long-term outcomes in cognitive functioning, psychiatric symptoms, and quality of life for individuals who had undergone ECT. METHODS: Eligible participants (N = 294) who completed a brief pre-ECT neuropsychological assessment within the last 14 years were recruited for a follow-up evaluation; a limited sample agreed to follow-up testing (n = 34). At follow-up, participants were administered cognitive measures (Repeatable Battery for the Assessment of Neuropsychological Status [RBANS], Wide Range Achievement Test-4 Word Reading, Trail Making Test, Wechsler Adult Intelligence Scale-Fourth Edition Letter Number Sequence and Digit Span, and Controlled Oral Word Association Test), along with emotional functioning measures (Beck Depression Inventory-Second Edition [BDI-II] and Beck Anxiety Inventory) and the World Health Organization Quality of Life-BREF quality of life measure. Follow-up-testing occurred on average (SD) 6.01 (3.5) years after last ECT treatment. RESULTS: At follow-up, a paired t test showed a large and robust reduction in mean BDI-II score. Scores in cognitive domains remained largely unchanged. A trend was observed for a mean reduction in RBANS visual spatial scores. Lower BDI-II scores were significantly associated with higher RBANS scores and improved quality of life. CONCLUSIONS: For some ECT patients, memory, cognitive functioning, and decreases in depressive symptoms can remain intact and stable even several years after ECT. However, the selective sampling at follow-up makes these results difficult to generalize to all post-ECT patients. Future research should examine what variables may predict stable cognitive functioning and a decline in psychiatric symptoms after ECT.

Cutting Edge: Engineering Active IKKß in T Cells Drives Tumor Rejection.

Acquired dysfunction of tumor-reactive T cells is one mechanism by which tumors can evade the immune system. Identifying and correcting pathways that contribute to such dysfunction should enable novel anticancer therapy design. During cancer growth, T cells show reduced NF-κB activity, which is required for tumor rejection. Impaired T cell-intrinsic NF-κB may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell-intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase ß (IKKß). T cell-restricted constitutively active IKKß augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control. Transfer of constitutively active IKKß-transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell-intrinsic NF-κB can result in tumor control, thus identifying a pathway with potential clinical applicability.

Unique Primary Care Needs of Transgender and Gender Non-Binary People.

It is important for the practicing primary care provider to become familiar with the unique health care needs for people who identify as transgender men, transgender women, and non-binary people, who are all within the scope of practice of a general obstetrician-gynecologist and other primary care providers. A review of the unique health needs and essential terminology is presented. This knowledge is a basic foundation to develop a welcoming and inclusive practice for people who are gender nonconforming. This fund of knowledge is essential the practicing primary care providers and support staff.

Developing an Inclusive and Welcoming LGBTQ Clinic.

People who identify as lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) are underserved and face barriers to knowledgeable health care. Most health systems are ill prepared to provide care that addresses the needs of the LGBTQ community. Basic steps to developing an LGBTQ welcoming health care program are presented. It can be adapted to diverse health care models, from obstetrics and gynecology and other primary care services whether public or private and to hospitals and specialty clinics. This LGBTQ inclusive health care model was developed in collaboration with the LGBTQ community, a multidisciplinary team of health care providers, and professionals of Law and Information Technology.

Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells.

T cells are essential for immune defenses against pathogens, such that viability of naïve T cells before antigen encounter is critical to preserve a polyclonal repertoire and prevent immunodeficiencies. The viability of naïve T cells before antigen recognition is ensured by IL-7, which drives expression of the prosurvival factor Bcl-2. Quiescent naïve T cells have low basal activity of the transcription factor NF-κB, which was assumed to have no functional consequences. In contrast to this postulate, our data show that basal nuclear NF-κB activity plays an important role in the transcription of IL-7 receptor α-subunit (CD127), enabling responsiveness of naïve T cells to the prosurvival effects of IL-7 and allowing T-cell persistence in vivo. Moreover, we show that this property of basal NF-κB activity is shared by mouse and human naïve T cells. Thus, NF-κB drives a distinct transcriptional program in T cells before antigen encounter by controlling susceptibility to IL-7. Our results reveal an evolutionarily conserved role of NF-κB in T cells before antigenic stimulation and identify a novel molecular pathway that controls T-cell homeostasis.

Transplantation tolerance after allograft rejection.

PURPOSE OF REVIEW: Although elusive for many decades, transplantation tolerance can now be achieved in the clinic. This has prompted follow-up investigations into its stability and longevity, as well as into barriers to its induction, which include memory T and B cells. RECENT FINDINGS: Clinical observations reveal that transplantation tolerance can be induced in adult recipients and that even episodes of acute rejection do not preclude successful weaning from immunosuppression to reveal tolerance. These observations appear to conflict with the currently accepted notion that adult transplant recipients harbor high frequencies of memory human leukocyte antigen-specific T cells that are a barrier to transplantation tolerance. We discuss how these observations may be rationalized, by proposing the generation of helpless effector CD8 T cells that cannot develop into memory, and by highlighting recent findings on the ability of transplantation tolerance to be spontaneously restored after rejection. We speculate that in individuals who develop tolerance while on immunosuppression and then experience rejection, it is this restored tolerance that is revealed upon successful weaning of immunosuppression. SUMMARY: We have reviewed clinical and experimental data to explain how transplantation tolerance may be achieved in individuals who have experienced allograft rejection.

Whole genome sequencing identifies a deletion in protein phosphatase 2A that affects its stability and localization in Chlamydomonas reinhardtii.

Whole genome sequencing is a powerful tool in the discovery of single nucleotide polymorphisms (SNPs) and small insertions/deletions (indels) among mutant strains, which simplifies forward genetics approaches. However, identification of the causative mutation among a large number of non-causative SNPs in a mutant strain remains a big challenge. In the unicellular biflagellate green alga Chlamydomonas reinhardtii, we generated a SNP/indel library that contains over 2 million polymorphisms from four wild-type strains, one highly polymorphic strain that is frequently used in meiotic mapping, ten mutant strains that have flagellar assembly or motility defects, and one mutant strain, imp3, which has a mating defect. A comparison of polymorphisms in the imp3 strain and the other 15 strains allowed us to identify a deletion of the last three amino acids, Y313F314L315, in a protein phosphatase 2A catalytic subunit (PP2A3) in the imp3 strain. Introduction of a wild-type HA-tagged PP2A3 rescues the mutant phenotype, but mutant HA-PP2A3 at Y313 or L315 fail to rescue. Our immunoprecipitation results indicate that the Y313, L315, or YFLΔ mutations do not affect the binding of PP2A3 to the scaffold subunit, PP2A-2r. In contrast, the Y313, L315, or YFLΔ mutations affect both the stability and the localization of PP2A3. The PP2A3 protein is less abundant in these mutants and fails to accumulate in the basal body area as observed in transformants with either wild-type HA-PP2A3 or a HA-PP2A3 with a V310T change. The accumulation of HA-PP2A3 in the basal body region disappears in mated dikaryons, which suggests that the localization of PP2A3 may be essential to the mating process. Overall, our results demonstrate that the terminal YFL tail of PP2A3 is important in the regulation on Chlamydomonas mating.

Obsessive-compulsive disorder symptoms and intrusive thoughts in the postpartum period: Associations with trauma exposure and PTSD symptoms.

In a community sample of trauma-exposed postpartum individuals (N = 167; mean age = 30, 90% White; 61.7% completed bachelor's degree or higher) longitudinally completed self-report measures on PTSD, depressive, and Obsessive-compulsive disorder (OCD) symptoms (specifically checking, ordering, washing, and obsessing symptoms), preoccupation with intrusive postpartum thoughts/neutralising strategies, and trauma exposure at 4 and 12 weeks postpartum. PTSD symptoms were strongly associated with all OCD symptoms (r = 0.32- 0.49, p < 0.001), preoccupation with postpartum-specific intrusive thoughts (r = 0.32-0.45, p < 0.001), and preoccupation with neutralising strategies (r = 0.21-0.29, p < 0.05) at both time points. PTSD symptoms were also predictive of checking and obsessing symptoms. This study identified PTSD symptoms as a new correlate for preoccupation with postpartum-specific intrusive thoughts and neutralising strategies in the postpartum period in a community sample. These findings add to the evidence suggesting a strong association between PTSD and OCD symptoms across the lifespan, including in non-clinical samples. Future research should examine best practices to assess and treat a variety of postpartum psychopathology symptoms, not just depression.

A panel network analysis of posttraumatic stress disorder and obsessive-compulsive disorder symptoms across the perinatal period.

The perinatal period is marked by a higher risk of experiencing depressive, anxiety, and/or trauma-related symptoms, a phenomenon that affects millions of individuals each year. Obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) symptoms commonly co-occur but have rarely been examined together beyond prevalence estimates in the perinatal period. Our study aimed to explore patterns of associations among OCD and PTSD symptoms to elucidate within- and between-person effects and how these effects may change over time. Participants (N = 270) were recruited during pregnancy from an academic medical center affiliated with a midwestern university. PTSD, OCD, and depressive symptoms were assessed at pregnancy, 4, 8, and 12 weeks postpartum. A panel graphical vector autoregression model was used to estimate networks. The temporal network provided information regarding directed predictive effects between symptoms, and hyperarousal, neutralizing, and ordering were the most stable and predictive symptoms across time. The contemporaneous network, which yields undirected partial correlations between symptoms at a given moment, indicated that there were positive associations between intrusions and avoidance, hyperarousal and negative alterations in cognitions and mood, as well as between hyperarousal and dysphoria. This study identified hyperarousal and neutralizing as the PTSD and OCD symptoms with the strongest stability, predictive power, and association with other symptoms. Clinically, this indicates that screening for hyperarousal and neutralizing symptoms may identify individuals who could maximally benefit from treatment in the perinatal period. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

From pregnancy to the postpartum: Unraveling the complexities of symptom profiles among trauma-exposed women.

BACKGROUND: Many women experience new onset or worsening of existing posttraumatic stress disorder (PTSD) symptoms during pregnancy and the early postpartum period. However, perinatal PTSD symptom profiles and their predictors are not well understood. METHODS: Participants (N = 614 community adults) completed self-report measures across three methodologically similar longitudinal studies. Mixture modeling was used to identify latent subgroups of trauma-exposed women with distinct patterns of symptoms at pregnancy, 1-month, and 3-month postpartum. RESULTS: Mixture modeling demonstrated two classes of women with relatively homogenous profiles (i.e., low vs. high symptoms) during pregnancy (n = 237). At 1-month postpartum (n = 391), results suggested a five-class solution: low symptoms, PTSD only, depression with primary appetite loss, depression, and comorbid PTSD and depression. At 3-months postpartum (n = 488), three classes were identified: low symptoms, elevated symptoms, and primary PTSD. Greater degree of exposure to interpersonal trauma and reproductive trauma, younger age, and minoritized racial/ethnic identity were associated with increased risk for elevated symptoms across the perinatal period. LIMITATIONS: Only a subset of potential predictors of PTSD symptoms were examined. Replication with a larger and more racially and ethnically diverse sample of pregnant women is needed. CONCLUSIONS: Results highlight limitations of current perinatal mental health screening practices, which could overlook women with elevations in symptoms (e.g., intrusions) that are not routinely assessed relative to others (e.g., depressed mood), and identify important risk factors for perinatal PTSD symptoms to inform screening and referral.

High TCR stimuli prevent induced regulatory T cell differentiation in a NF-κB-dependent manner.

The concentration of Ag or mitogenic stimuli is known to play an important role in controlling the differentiation of naive CD4(+) T cells into different effector phenotypes. In particular, whereas TCR engagement at low Ag doses in the presence of TGF-ß and IL-2 can promote differentiation of Foxp3-expressing induced regulatory T cells (iTregs), high levels of Ag have been shown in vitro and in vivo to prevent Foxp3 upregulation. This tight control of iTreg differentiation dictated by Ag dose most likely determines the quality and duration of an immune response. However, the molecular mechanism by which this high-dose inhibition of Foxp3 induction occurs is not well understood. In this study, we demonstrate that when cells are in the presence of CD28 costimulation, TCR-dependent NF-κB signaling is essential for Foxp3 inhibition at high doses of TCR engagement in mouse T cells. Prevention of Foxp3 induction depends on the production of NF-κB-dependent cytokines by the T cells themselves. Moreover, T cells that fail to upregulate Foxp3 under iTreg-differentiating conditions and high TCR stimulation acquire the capacity to make TNF and IFN-γ, as well as IL-17 and IL-9. Thus, NF-κB helps T cells control their differentiation fate in a cell-intrinsic manner and prevents peripheral iTreg development under conditions of high Ag load that may require more vigorous effector T cell responses.