Primary differentiated respiratory epithelial cells respond to apical measles virus infection by shedding multinucleated giant cells.

Measles virus (MeV) is highly infectious by the respiratory route and remains an important cause of childhood mortality. However, the process by which MeV infection is efficiently established in the respiratory tract is controversial with suggestions that respiratory epithelial cells are not susceptible to infection from the apical mucosal surface. Therefore, it has been hypothesized that infection is initiated in lung macrophages or dendritic cells and that epithelial infection is subsequently established through the basolateral surface by infected lymphocytes. To better understand the process of respiratory tract initiation of MeV infection, primary differentiated respiratory epithelial cell cultures were established from rhesus macaque tracheal and nasal tissues. Infection of these cultures with MeV from the apical surface was more efficient than from the basolateral surface with shedding of viable MeV-producing multinucleated giant cell (MGC) syncytia from the surface. Despite presence of MGCs and infectious virus in supernatant fluids after apical infection, infected cells were not detected in the adherent epithelial sheet and transepithelial electrical resistance was maintained. After infection from the basolateral surface, epithelial damage and large clusters of MeV-positive cells were observed. Treatment with fusion inhibitory peptides showed that MeV production after apical infection was not dependent on infection of the basolateral surface. These results are consistent with the hypothesis that MeV infection is initiated by apical infection of respiratory epithelial cells with subsequent infection of lymphoid tissue and systemic spread.

Cutaneous T-cell lymphoma of the eyelid masquerading as dermatitis.

Cutaneous T-cell lymphoma (CTCL) may pose a diagnostic challenge for physicians, as clinical presentation and histologic analysis may mimic benign dermatologic conditions. The authors present a case of recurrent CTCL in which the recurrence was limited to the eyelid and misdiagnosed as a contact dermatitis. To the best of the authors' knowledge, this is the first reported case of recurrent CTCL that has presented solely as dermatitis of the eyelid.

Modeling the measles paradox reveals the importance of cellular immunity in regulating viral clearance.

Measles virus (MV) is a highly contagious member of the Morbillivirus genus that remains a major cause of childhood mortality worldwide. Although infection induces a strong MV-specific immune response that clears viral load and confers lifelong immunity, transient immunosuppression can also occur, leaving the host vulnerable to colonization from secondary pathogens. This apparent contradiction of viral clearance in the face of immunosuppression underlies what is often referred to as the 'measles paradox', and remains poorly understood. To explore the mechanistic basis underlying the measles paradox, and identify key factors driving viral clearance, we return to a previously published dataset of MV infection in rhesus macaques. These data include virological and immunological information that enable us to fit a mathematical model describing how the virus interacts with the host immune system. In particular, our model incorporates target cell depletion through infection of host immune cells-a hallmark of MV pathology that has been neglected from previous models. We find the model captures the data well, and that both target cell depletion and immune activation are required to explain the overall dynamics. Furthermore, by simulating conditions of increased target cell availability and suppressed cellular immunity, we show that the latter causes greater increases in viral load and delays to MV clearance. Overall, this signals a more dominant role for cellular immunity in resolving acute MV infection. Interestingly, we find contrasting dynamics dominated by target cell depletion when viral fitness is increased. This may have wider implications for animal morbilliviruses, such as canine distemper virus (CDV), that cause fatal target cell depletion in their natural hosts. To our knowledge this work represents the first fully calibrated within-host model of MV dynamics and, more broadly, provides a new platform from which to explore the complex mechanisms underlying Morbillivirus infection.

Plasma Cytokines and Chemokines in Zambian Children With Measles: Innate Responses and Association With HIV-1 Coinfection and In-Hospital Mortality.

To identify immune factors present during the acute rash phase of measles and associations with outcome and human immunodeficiency virus type 1 (HIV-1) coinfection, we measured the plasma levels of 22 cytokines and chemokines in Zambian children hospitalized with measles (n = 148) and control children (n = 44). Children with measles had higher levels of innate cytokines tumor necrosis factor (TNF) α, interleukin 1ß (IL-1ß), interleukin 18, and interleukin 6; chemokines CCL2, CCL4, CCL11, CCL22, CXCL8, and CXCL10; and T-cell cytokines interferon γ, and interleukin 2, 10, and 17. Children who died in the hospital had higher levels of TNF-α, IL-1ß, interleukin 12p70; CCL2, CCL4, CCL13, CCL17, CXCL8, CXCL10; and interleukin 2 and interferon γ than children who survived, and lower levels of interleukin 4. Children coinfected with HIV-1 had higher levels of TNF-α and IL-1ß than HIV-uninfected children with measles, and lower levels of interleukin 4 and 5. Therefore, acute measles was characterized by activation of macrophages and T cells producing type 1, but not type 2, cytokines, which was more pronounced in fatal disease.

Cutting edge: CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal.

Central memory (CM) CD8(+) T cells "remember" prior encounters because they maintain themselves through cell division in the absence of ongoing challenge (homeostatic self-renewal), as well as reproduce the CM fate while manufacturing effector cells during secondary Ag encounters (rechallenge self-renewal). We tested the consequence of conditional deletion of the bone marrow homing receptor CXCR4 on antiviral T cell responses. CXCR4-deficient CD8(+) T cells have impaired memory cell maintenance due to defective homeostatic proliferation. Upon rechallenge, however, CXCR4-deficient T cells can re-expand and renew the CM pool while producing secondary effector cells. The critical bone marrow-derived signals essential for CD8(+) T cell homeostatic self-renewal appear to be dispensable to yield self-renewing, functionally asymmetric cell fates during rechallenge.

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics.

Measles virus (MeV) is the poster child for acute infection followed by lifelong immunity. However, recent work shows the presence of MeV RNA in multiple sites for up to 3 mo after infection in a proportion of infected children. Here, we use experimental infection of rhesus macaques to show that prolonged RNA presence is characteristic of primary infection. We found that viral RNA persisted in the blood, respiratory tract, or lymph nodes four to five times longer than the infectious virus and that the clearance of MeV RNA from blood happened in three phases: rapid decline coincident with clearance of infectious virus, a rebound phase with increases up to 10-fold, and a phase of slow decrease to undetectable levels. To examine the effect of individual host immune factors on MeV load dynamics further, we developed a mathematical model that expressed viral replication and elimination in terms of the strength of MeV-specific T-cell responses, antibody responses, target cell limitations, and immunosuppressive activity of regulatory T cells. Based on the model, we demonstrate that viral dynamics, although initially regulated by T cells, require antibody to eliminate viral RNA. These results have profound consequences for our view of acute viral infections, the development of prolonged immunity, and, potentially, viral evolution.

Vaxfectin adjuvant improves antibody responses of juvenile rhesus macaques to a DNA vaccine encoding the measles virus hemagglutinin and fusion proteins.

DNA vaccines formulated with the cationic lipid-based adjuvant Vaxfectin induce protective immunity in macaques after intradermal (i.d.) or intramuscular (i.m.) delivery of 0.5 to 1 mg of codon-optimized DNA encoding the hemagglutinin (H) and fusion (F) proteins of measles virus (MeV). To characterize the effect of Vaxfectin at lower doses of H+F DNA, rhesus macaques were vaccinated twice with 20 µg of DNA plus Vaxfectin i.d., 100 µg of DNA plus Vaxfectin i.d., 100 µg of DNA plus Vaxfectin i.m. or 100 µg of DNA plus phosphate-buffered saline (PBS) i.m. using a needleless Biojector device. The levels of neutralizing (P = 0.036) and binding (P = 0.0001) antibodies were higher after 20 or 100 µg of DNA plus Vaxfectin than after 100 µg of DNA plus PBS. Gamma interferon (IFN-γ)-producing T cells were induced more rapidly than antibody, but were not improved with Vaxfectin. At 18 months after vaccination, monkeys were challenged with wild-type MeV. None developed rash or viremia, but all showed evidence of infection. Antibody levels increased, and IFN-γ- and interleukin-17-producing T cells, including cells specific for the nucleoprotein absent from the vaccine, were induced. At 3 months after challenge, MeV RNA was detected in the leukocytes of two monkeys. The levels of antibody peaked 2 to 4 weeks after challenge and then declined in vaccinated animals reflecting low numbers of bone marrow-resident plasma cells. Therefore, Vaxfectin was dose sparing and substantially improved the antibody response to the H+F DNA vaccine. This immune response led to protection from disease (rash/viremia) but not from infection. Antibody responses after challenge were more transient in vaccinated animals than in an unvaccinated animal.

Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells.

The ability of activated progenitor T cells to self-renew while producing differentiated effector cell descendants may underlie immunological memory and persistent responses to ongoing infection. The nature of stem-like T cells responding to cancer and during treatment with immunotherapy is not clear. The subcellular organization of dividing progenitor CD8+ T cells from mice challenged with syngeneic tumors is examined here. Three-dimensional microscopy reveals an activating hub composed of polarized CD3, CD28, and phosphatidylinositol 3-kinase (PI3K) activity at the putative immunological synapse with an inhibitory hub composed of polarized PD-1 and CD73 at the opposite pole of mitotic blasts. Progenitor T cells from untreated and inhibitory checkpoint blockade-treated mice yield a differentiated TCF1- daughter cell, which inherits the PI3K activation hub, alongside a discordantly fated, self-renewing TCF1+ sister cell. Dynamic organization of opposite activating and inhibitory signaling poles in mitotic lymphocytes may account for the enigmatic durability of specific immunity.

Inflammation and Mortality in COVID-19 Hospitalized Patients With and Without Type 2 Diabetes.

CONTEXT: COVID-19 mortality is increased in patients with diabetes. A common hypothesis is that the relationship of inflammation with COVID-19 mortality differs by diabetes status. OBJECTIVE: The aim of this study was to determine the relationship of inflammation with mortality in COVID-19 hospitalized patients and to assess if the relationship differs by strata of type 2 diabetes status. METHODS: A case-control (died-survived) study of 538 COVID-19 hospitalized patients, stratified by diabetes status, was conducted at Columbia University Irving Medical Center. We quantified the levels of 8 cytokines and chemokines in serum, including interferon (IFN)-α2, IFN-γ, interleukin (IL)-1α, IL-1ß, IL-6, IL-8/CXCL8, IFNγ-induced protein 10 (IP10)/CXCL10 and tumor necrosis factor α (TNF-α) using immunoassays. Logistic regression models were used to model the relationships of log-transformed inflammatory markers (or their principal components) and mortality. RESULTS: In multiple logistic regression models, higher serum levels of IL-6 (adjusted odds ratio [aOR]:1.74, 95% CI [1.48, 2.06]), IL-8 (aOR: 1.75 [1.41, 2.19]) and IP10 (aOR: 1.36 [1.24, 1.51]), were significantly associated with mortality. This association was also seen in second principal component with loadings reflecting similarities among these 3 markers (aOR: 1.88 [1.54-2.31]). Significant positive association of these same inflammatory markers with mortality was also observed within each strata of diabetes. CONCLUSION: We show that mortality in COVID-19 patients is associated with elevated serum levels of innate inflammatory cytokine IL-6 and inflammatory chemokines IL-8 and IP10. This relationship is consistent across strata of diabetes, suggesting interventions targeting these innate immune pathways could potentially also benefit patients with diabetes.

Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia.

Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5'-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse. SIGNIFICANCE: Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.

Oncogenic Vav1-Myo1f induces therapeutically targetable macrophage-rich tumor microenvironment in peripheral T cell lymphoma.

Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) comprises heterogeneous lymphoid malignancies characterized by pleomorphic lymphocytes and variable inflammatory cell-rich tumor microenvironment. Genetic drivers in PTCL-NOS include genomic alterations affecting the VAV1 oncogene; however, their specific role and mechanisms in PTCL-NOS remain incompletely understood. Here we show that expression of Vav1-Myo1f, a recurrent PTCL-associated VAV1 fusion, induces oncogenic transformation of CD4+ T cells. Notably, mouse Vav1-Myo1f lymphomas show T helper type 2 features analogous to high-risk GATA3+ human PTCL. Single-cell transcriptome analysis reveals that Vav1-Myo1f alters T cell differentiation and leads to accumulation of tumor-associated macrophages (TAMs) in the tumor microenvironment, a feature linked with aggressiveness in human PTCL. Importantly, therapeutic targeting of TAMs induces strong anti-lymphoma effects, highlighting the lymphoma cells' dependency on the microenvironment. These results demonstrate an oncogenic role for Vav1-Myo1f in the pathogenesis of PTCL, involving deregulation in T cell polarization, and identify the lymphoma-associated macrophage-tumor microenvironment as a therapeutic target in PTCL.

Approaching the Interpretation of Discordances in SARS-CoV-2 Testing.

The coronavirus disease 2019 pandemic has upended life throughout the globe. Appropriate emphasis has been placed on developing effective therapies and vaccines to curb the pandemic. While awaiting such countermeasures, mitigation efforts coupled with robust testing remain essential to controlling spread of the disease. In particular, serological testing plays a critical role in providing important diagnostic, prognostic, and therapeutic information. However, this information is only useful if the results can be accurately interpreted. This pandemic placed clinical testing laboratories and requesting physicians in a precarious position because we are actively learning about the disease and how to interpret serological results. Having developed robust assays to detect antibodies generated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and serving the hardest-hit areas within the New York City epicenter, we found 3 types of discordances in SARS-CoV-2 test results that challenge interpretation. Using representative clinical vignettes, these interpretation dilemmas are highlighted, along with suggested approaches to resolve such cases.

FYN-TRAF3IP2 induces NF-κB signaling-driven peripheral T cell lymphoma.

Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack driver actionable targets for directed therapies in most cases. Here we identify FYN-TRAF3IP2 as a recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, we show that FYN-TRAF3IP2 leads to aberrant NF-κB signaling downstream of T cell receptor activation. Consistent with a driver oncogenic role, FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Moreover, abrogation of NF-κB signaling in FYN-TRAF3IP2-induced tumors with IκB kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results demonstrate an oncogenic and pharmacologically targetable role for FYN-TRAF3IP2 in PTCLs and call for the clinical testing of anti-NF-κB targeted therapies in these diseases.

A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19.

BACKGROUNDAlthough convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.METHODSWe conducted a randomized, double-blind, controlled trial among adults hospitalized with severe and critical COVID-19 at 5 sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized 2:1 to receive a single transfusion of either convalescent plasma or normal control plasma. The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.RESULTSOf 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to receive normal control plasma. At 28 days, no significant improvement in the clinical scale was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval [CI] 0.83-2.68, P = 0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22-0.91, P = 0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.CONCLUSIONIn adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in day 28 clinical status. However, convalescent plasma was associated with significantly improved survival. A possible explanation is that survivors remained hospitalized at their baseline clinical status.TRIAL REGISTRATIONClinicalTrials.gov, NCT04359810.FUNDINGAmazon Foundation, Skoll Foundation.

A durable protective immune response to wild-type measles virus infection of macaques is due to viral replication and spread in lymphoid tissues.

Infection with wild-type (WT) measles virus (MeV) is an important cause of childhood mortality that leads to lifelong protective immunity in survivors. WT MeV and the live-attenuated MeV used in the measles vaccine (LAMV) are antigenically similar, but the determinants of attenuation are unknown, and protective immunity induced by LAMV is less robust than that induced by WT MeV. To identify factors that contribute to these differences, we compared virologic and immunologic responses after respiratory infection of rhesus macaques with WT MeV or LAMV. In infected macaques, WT MeV replicated efficiently in B and T lymphocytes with spreading throughout lymphoid tissues resulting in prolonged persistence of viral RNA. In contrast, LAMV replicated efficiently in the respiratory tract but displayed limited spread to lymphoid tissue or peripheral blood mononuclear cells. In vitro, WT MeV and LAMV replicated similarly in macaque primary respiratory epithelial cells and human lymphocytes, but LAMV-infected lymphocytes produced little virus. Plasma concentrations of interleukin-1ß (IL-1ß), IL-12, interferon-γ (IFN-γ), CCL2, CCL11, CXCL9, and CXCL11 increased in macaques after WT MeV but not LAMV infection. WT MeV infection induced more protective neutralizing, hemagglutinin-specific antibodies and bone marrow plasma cells than did LAMV infection, although numbers of MeV-specific IFN-γ- and IL-4-producing T cells were comparable. Therefore, MeV attenuation may involve altered viral replication in lymphoid tissue that limited spread and decreased the host antibody response, suggesting a link between lifelong protective immunity and the ability of WT MeV, but not LAMV, to spread in lymphocytes.

Association of persistent wild-type measles virus RNA with long-term humoral immunity in rhesus macaques.

Recovery from measles results in life-long protective immunity. To understand induction of long-term immunity, rhesus macaques were studied for 6 months after infection with wild-type measles virus (MeV). Infection caused viremia and rash, with clearance of infectious virus by day 14. MeV RNA persisted in PBMCs for 30-90 days and in lymphoid tissue for 6 months most often in B cells but was rarely detected in BM. Antibody with neutralizing activity and binding specificity for MeV nucleocapsid (N), hemagglutinin (H), and fusion proteins appeared with the rash and avidity matured over 3-4 months. Lymph nodes had increasing numbers of MeV-specific antibody-secreting cells (ASCs) and germinal centers with late hyalinization. ASCs appeared in circulation with the rash and continued to appear along with peripheral T follicular helper cells for the study duration. ASCs in lymph nodes and PBMCs produced antibody against both H and N, with more H-specific ASCs in BM. During days 14-21, 20- to 100-fold more total ASCs than MeV-specific ASCs appeared in circulation, suggesting mobilization of preexisting ASCs. Therefore, persistence of MeV RNA in lymphoid tissue was accompanied by continued germinal center formation, ASC production, avidity maturation, and accumulation of H-specific ASCs in BM to sustain neutralizing antibody and protective immunity.

Understanding the causes and consequences of measles virus persistence.

Measles is an acute systemic viral disease with initial amplification of infection in lymphoid tissue and subsequent spread over 10-14 days to multiple organs. Failure of the innate response to control initial measles virus (MeV) replication is associated with the ability of MeV to inhibit the induction of type I interferon and interferon-stimulated antiviral genes. Rather, the innate response is characterized by the expression of proteins regulated by nuclear factor kappa B and the inflammasome. With eventual development of the adaptive response, the rash appears with immune cell infiltration into sites of virus replication to initiate the clearance of infectious virus. However, MeV RNA is cleared much more slowly than recoverable infectious virus and remains present in lymphoid tissue for at least 6 months after infection. Persistence of viral RNA and protein suggests persistent low-level replication in lymphoid tissue that may facilitate maturation of the immune response, resulting in lifelong protection from reinfection, while persistence in other tissues (for example, the nervous system) may predispose to development of late disease such as subacute sclerosing panencephalitis. Further studies are needed to identify mechanisms of viral clearance and to understand the relationship between persistence and development of lifelong immunity.

Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway.

Unequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co-localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation. Perturbation of class I PI3K activity disrupts asymmetry of upstream antigen receptors and downstream glucose transporter traffic. The roles of PI3K signaling in nutrient utilization, proliferation, and gene expression may have converged with the conserved role of PI3K signaling in cellular symmetry breaking to form a logic for regenerative lymphocyte divisions.

Lymphocyte Fate and Metabolism: A Clonal Balancing Act.

Activated lymphocytes perform a clonal balancing act, yielding a daughter cell that differentiates owing to intense PI3K signaling, alongside a self-renewing sibling cell with blunted anabolic signaling. Divergent cellular anabolism versus catabolism is emerging as a feature of several developmental and regenerative paradigms. Metabolism can dictate cell fate, in part, because lineage-specific regulators are embedded in the circuitry of conserved metabolic switches. Unequal transmission of PI3K signaling during regenerative divisions is reminiscent of compartmentalized PI3K activity during directed motility or polarized information flow in non-dividing cells. The diverse roles of PI3K pathways in membrane traffic, cell polarity, metabolism, and gene expression may have converged to instruct sibling cell feast and famine, thereby enabling clonal differentiation alongside self-renewal.

IRF4 Couples Anabolic Metabolism to Th1 Cell Fate Determination.

Anabolic metabolism in lymphocytes promotes plasmablast and cytotoxic T cell differentiation at the expense of self-renewal. Heightened expression and function of the transcription factor IFN regulatory factor 4 (IRF4) accompany enhanced anabolic induction and full commitment to functional differentiation in B cells and CD8+ T cells. In this study, we used a genetic approach to determine whether IRF4 plays an analogous role in Th1 cell induction. Our findings indicate that IRF4 promotes determined Th1 cell differentiation in tandem with anabolic metabolism of CD4+ T cells. IRF4-deficient CD4+ T cells stimulated in vitro exhibit impaired induction of Th1 gene expression and defective silencing of T cell factor 1 expression. IRF4-deficient CD4+ T cells also undergo a shift toward catabolic metabolism, with reduced mammalian target of rapamycin activation, cell size, and nutrient uptake, as well as increased mitochondrial clearance. These findings suggest that the ability to remodel metabolic states can be an essential gateway for altering cell fate.