Hu T, Zhu Z, Luo Y
… +6 more, Wizzard S, Hoar J, Shinde SS, Yihunie K, Yao C, Wu T
Nat Immunol
· 2026 Mar · PMID 41545542
·
Full text
Stem-like T cells promote the efficacy of immunotherapy and are heterogeneous in stemness, with long-term (LT) stem-like T cells at the apex of this hierarchy. How the stemness hierarchy is regulated in chimeric antigen...Stem-like T cells promote the efficacy of immunotherapy and are heterogeneous in stemness, with long-term (LT) stem-like T cells at the apex of this hierarchy. How the stemness hierarchy is regulated in chimeric antigen receptor (CAR) T cells and how it affects antitumor function are unclear. Here we show that BACH2 dose-dependently regulates LT stem-like differentiation and antitumor immunity of CAR T cells. LT stem-like CAR T cells that appear before infusion and re-emerge after tumor clearance have superior antitumor immunity and the greatest BACH2 expression. BACH2 promotes the antitumor response of CAR T cells and the LT stem-like transcriptional program. Temporal and quantitative induction of BACH2 expression in CAR T cells during manufacturing using chemical switches fine-tunes the degree of stemness and imprints greater control of solid tumors. Together, these data show that BACH2 dosage defines stemness hierarchy in CAR T cells and can be temporally and tunably controlled to optimize differentiation and antitumor efficacy.
Conti AG, Evans AC, von Linde T
… +22 more, Deguit CDT, Whiteside SK, Wesolowski AJ, Imianowski CJ, Yamashita-Kanemaru Y, Dahmani L, Chapman J, Pillay AM, Al-Deka A, Greaves R, Burton O, Vardaka P, Sampurno S, Pérez-Núñez I, Saw NYL, Yang J, Howden AJM, Okkenhaug K, Mitra S, Swiatczak B, Parish IA, Roychoudhuri R
Nat Immunol
· 2026 Mar · PMID 41545541
·
Full text
Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states....Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.
Chang TC, Heard A, Lattin J
… +23 more, Warrington JM, Barrett A, Landmann JH, Tenzin Y, Ganesh V, Thompson B, Afrin S, Gupta DK, Chang JF, Ritchey J, Selli ME, Hsu YS, Song H, Federico AJ, Horn A, Meers MP, Weber EW, Wandless TJ, Crawford JC, Thomas PG, DiPersio JF, Gottschalk S, Singh N
Nat Immunol
· 2026 Mar · PMID 41545540
·
Full text
Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the ex...Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.
Vatovec T, Neehus AL, Jackson KJL
… +83 more, Avery DT, Bagarić I, Erazo L, Arango-Franco CA, Ogishi M, Ahmed SF, Cederholm A, Russell AJ, Della Mina E, Al-Rifai D, Bull R, Buetow L, Sobrino S, Zhang A, Wahlster L, Michelet M, Parvaneh N, Peel J, Barzaghi F, Leardini D, Philippot Q, Saettini F, Dutrieux J, de Muylder B, Vendemini F, Baccelli F, Catala A, Gambineri E, Veltroni M, Pandiarajan V, Aguilar Y, Haerynck F, Elliott M, Turville S, Brillot F, Khan T, Consonni F, Berteloot L, Sewell WA, Rao G, Largeaud L, Conti F, Roullion C, Masson C, Pegoraro F, Ye T, Joubran S, Villalpando E, Bessot B, Seeleuthner Y, Le Voyer T, Rosain J, Li H, Janda Z, Muratore E, Soudée C, Delabesse E, Goulvestre C, Shahrooei M, Puel A, André I, Bole-Feysot C, Abel L, Erlacher M, Béziat V, Lagresle-Peyrou C, Cheynier R, Six E, Marr N, Pasquet M, Alsina L, Goodnow CC, Landegren N, Aiuti A, Zhang P, Masetti R, Huang DT, Ma CS, Casanova JL, Sankaran VG, Bustamante J, Tangye SG, Bohlen J
Nat Immunol
· 2026 Feb · PMID 41540267
·
Full text
The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK...The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis and dysregulated B cell receptor signaling. CBL deficiency impairs humoral immunity by limiting memory B cell formation and reducing class switching and somatic hypermutation. Consequently, antigen-specific B cell generation and adaptive immune memory are disrupted, predisposing individuals to infection. Human CBL is critical for B cell development and function but redundant for T cell biology.
Sonner JK, Kahn A, Binkle-Ladisch L
… +29 more, Engler JB, Haack B, Zeiler C, Unger L, Bauer S, Fischbach F, Almanzar G, Walkenhorst M, Mayer C, Kolakowska A, Graute S, Ramien C, Winschel I, Rothammer N, Heine M, Horneffer-van der Sluis V, Thiemann V, Vieira V, Meurs N, Renné T, Prelog M, Jørgensen SB, Seeley RJ, Diemert A, Arck PC, Gold SM, Heeren J, Wischhusen J, Friese MA
Nat Immunol
· 2026 Mar · PMID 41540266
·
Full text
Inflammatory activity during multiple sclerosis (MS) often improves during pregnancy, suggesting that pregnancy-related immune adaptations affect the disease. Here we show that growth/differentiation factor-15 (GDF-15) i...Inflammatory activity during multiple sclerosis (MS) often improves during pregnancy, suggesting that pregnancy-related immune adaptations affect the disease. Here we show that growth/differentiation factor-15 (GDF-15) increases during pregnancy and correlates with a reduced rate of MS relapses. GDF-15 also accumulates in the inflamed central nervous system, and its absence impairs inflammation resolution in a mouse model of MS. GDF-15 suppresses autoimmune T cell responses through an indirect signaling pathway involving the activation of GDNF family receptor α-like (GFRAL) on brainstem neurons. Therapeutic approaches, including neuronal gene delivery, recombinant GDF-15 administration and targeted chemogenetic activation of GFRAL-positive neurons induce β-adrenergic signaling and norepinephrine synthesis in the spleen, leading to decreased expression of integrins on T cells required for transmigration across the blood-brain barrier and confer protection against neuroinflammation in preclinical models of MS. These findings position GDF-15 as a crucial neuroimmune mediator and the GDF-15-GFRAL axis as promising target for MS.
Bhamidipati K, McIntyre ABR, Kazerounian S
… +30 more, Ce G, Wong SW, Tran M, Prell SA, Lau R, Khedgikar V, Altmann C, Small A, Madhu R, Presti SR, Anufrieva KS, Blazar PE, Lange JK, Seifert JA, Accelerating Medicines Partnership RA/SLE Network, Accelerating Medicines Partnership: Autoimmune and Immune-Mediated Diseases Network (AMP-AIM), Colorado Interdisciplinary Joint Biology Program (CUIJBP) Consortium, Moreland LW, Croft AP, Smith MH, Donlin LT, Lewis MJ, Jonsson AH, Pitzalis C, Thomas R, Gravallese EM, Brenner MB, Korsunsky I, Wechalekar MD, Wei K
Nat Immunol
· 2026 Mar · PMID 41540265
·
Full text
Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the underlying mechanisms are poorly understood. To identify molecular determinants of refractory RA, we performed spatial transcriptomic profilin...Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the underlying mechanisms are poorly understood. To identify molecular determinants of refractory RA, we performed spatial transcriptomic profiling on synovial tissue biopsy samples taken 6 months before and after treatment. In the baseline biopsy samples of non-remitting patients, we identified increased fibrogenic signaling within vascular tissue niches, marked by high fibroblast COMP expression. We uncovered a role of endothelial-derived Notch signaling as an upstream regulator of fibroblast transforming growth factor beta (TGFβ) signaling via its opposing ability to induce TGFβ isoform expression while suppressing TGFβ receptors, generating a proximal-to-distal gradient of TGFβ sensitivity that can be altered with disruption of steady-state Notch signaling. In posttreatment biopsy samples, we observed significant immune depletion with expansion of fibrogenic niches, a process that can be reversed by inhibition of Notch and TGFβ signaling in RA patient-derived organoids. Collectively, our data implicate targeting of TGFβ signaling to prevent exuberant synovial tissue fibrosis as a potential therapeutic strategy for refractory RA.
Stier MT, Sewell AE, Mwizerwa EL
… +13 more, Sim CY, Tanner SM, Nichols CM, Durai HH, Jennings EQ, Lindau P, Wilfong EM, Obeidalla SN, Kerchberger VE, Newcomb DC, Bastarache JA, Ware LB, Rathmell JC
Nat Immunol
· 2026 Feb · PMID 41540263
·
Full text
Metabolic and immunologic dysfunction, including pathological CD4 T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we c...Metabolic and immunologic dysfunction, including pathological CD4 T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults. CD4 T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (T) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted T cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of T cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in T cells. These findings indicate that metabolic dysfunction was a contributor to CD4 T cell remodeling in critical illness and suggest avenues to restore effective immunity.
Kumar S, Li C, Zhou L
… +23 more, Zhan Q, Alaswad A, Volland S, Costa B, Krooss SA, Klefenz I, Schmaus H, Zeuzem A, von Witzendorff D, Lickei H, Pueschel L, Kraft ARM, Cornberg M, Koczulla AR, Pink I, Hoeper MM, Xu CJ, Häussler S, Wiestler M, Netea MG, Illig T, Sun J, Li Y
Nat Immunol
· 2026 Feb · PMID 41535626
·
Full text
The mechanisms driving immune dysregulation in long COVID disease remain elusive. Here we integrated single-cell multiome data, immunological profiling and functional assays to investigate immune alterations across multi...The mechanisms driving immune dysregulation in long COVID disease remain elusive. Here we integrated single-cell multiome data, immunological profiling and functional assays to investigate immune alterations across multiple cohorts. A transcriptional state in circulating monocytes (LC-Mo) was enriched in individuals with mild-moderate acute infection and accompanied by persistent elevations of plasma CCL2, CXCL11 and TNF. LC-Mo showed TGFβ and WNT-β-catenin signaling and correlated with fatigue severity. Protein markers of LC-Mo were increased in individuals with pronounced fatigue or dyspnea, and those with severe respiratory symptoms showed higher LC-Mo expression. Epigenetically, LC-Mo exhibited AP-1- and NF-κB1-driven profibrotic programs. LC-Mo-like macrophages in bronchoalveolar lavage samples from individuals with severe respiratory symptoms displayed a profibrotic profile, and individuals with a high LC-Mo transcriptional state showed impaired interferon responses after stimulation. Collectively, our findings define a pathogenic monocyte transcriptional state linking systemic immune dysfunction to persistent long COVID disease, providing mechanistic insights and potential therapeutic targets.
Park SL, Painter MM, Manne S
… +30 more, Alcalde V, McLaughlin M, Sullivan MA, Mathew D, Torres L, Huang YJ, Reeg DB, Douek NR, Campos T, Klapholz M, Cardenas MA, Fang V, Ngiow SF, Kc W, Goel RR, Baxter AE, Wu JE, Tan M, Berry CT, Ellebrecht CT, Huang AC, Papazian E, Liu Y, Rajasekaran K, Brody RM, Thaler ER, Basu D, Diab A, Giles JR, Wherry EJ
Nat Immunol
· 2026 Feb · PMID 41530424
·
Full text
Follicular regulatory T (T) cells restrain follicular helper T (T) cell-mediated B cell responses to optimize humoral immunity while limiting autoimmunity. Here we assessed the developmental dynamics of T cells. We found...Follicular regulatory T (T) cells restrain follicular helper T (T) cell-mediated B cell responses to optimize humoral immunity while limiting autoimmunity. Here we assessed the developmental dynamics of T cells. We found that T cells undergo progressive differentiation through progenitor, early effector and late effector stages. Late effector T cells possessed inherent instability, and could lose expression of FoxP3 to become ExT cells. Expression of effector T programs in T cells preceded instability, a process that was mediated by Tcf7. A subset of ExT could be redeemed by re-expression of FoxP3. Extrinsically, T cells enhanced late effector T cell differentiation by diverting cells away from a default Prdm1/Blimp-1 fate to express Bcl6. Together, these data indicate that T cells are a dynamic and plastic cell subset, the differentiation of which is controlled by intrinsic and extrinsic programs that work together to form a feedback loop to control humoral immunity.
Traboulsi W, Gaur P, Kundu S
… +14 more, Ramlaoui Z, Priestley-Milianta C, Iyengar A, Shobaki N, Sarhan D, Lee MJ, Lee JM, Pavlakis GN, Mkrtichyan M, Valge-Archer VE, Barry ST, Verma V, Gupta S, Khleif SN
CD8 central memory T (T) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8 T cells with superior...CD8 central memory T (T) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8 T cells with superior memory by activating the SIRT-1-FOXO1 pathway and inducing metabolic and transcriptional switches through inhibition of enzymatic activity and enhanced PARP trapping. Together, this results in suppression of the cell cycle and upregulation of memory and fatty acid oxidation gene expression, and reprogramming CD8 T cells into T cells with enhanced metabolic fitness and substantially higher recall capabilities. PARP inhibitor treatment of tumor-bearing mice resulted in an increase in the number of 'superior T' cells within the tumor microenvironment and enhanced immune-mediated antitumor responses. PARP inhibitor-treated CD8 T cells were more effective in adoptive cell therapy. Furthermore, the frequency of CD8 memory T cells and the expression of their memory markers was increased in patients with cancer treated with PARP inhibitor. Together, these data show that PARP inhibition directly reprograms CD8 T cells, enhancing metabolic fitness and generating highly effective therapeutically superior memory cells.
Eosinophils are multifunctional granulocytes involved in immune regulation, metabolism and tissue repair; however, the extent of their heterogeneity across tissues and the principles governing their specialization are no...Eosinophils are multifunctional granulocytes involved in immune regulation, metabolism and tissue repair; however, the extent of their heterogeneity across tissues and the principles governing their specialization are not well defined. Here, we present a single-cell transcriptomic and proteomic atlas of mouse eosinophils spanning immune, barrier and metabolic sites. By integrating transcriptional profiling, high-dimensional surface proteomics and in vivo fate mapping, we show that eosinophil identity is shaped by both tissue-derived cues and the duration of local residency. Long-lived eosinophils in the small intestine diversify into transcriptionally and phenotypically distinct subsets, whereas short-lived and intermediate-lived populations in the lungs and colon, respectively, remain comparatively uniform. We identify trajectory-associated surface markers that stratify eosinophil maturation from bone-marrow progenitors to long-term tissue-resident subsets. This atlas establishes a unified framework in which tissue-specific residency time drives eosinophil maturation and diversification, providing a molecular toolkit for resolving eosinophil states in health and disease.
Dendritic cells are essential for establishing thymic central tolerance; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we id...Dendritic cells are essential for establishing thymic central tolerance; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we identify seven thymic conventional dendritic cell (cDC) subsets and discriminate their abilities to present self-antigens and induce regulatory T cells. Mice blocked at different stages of T cell development revealed that CD4 single-positive (CD4SP) and CD8SP thymocytes differentially support homeostasis and activation of type 1 cDCs (cDC1s) versus cDC2s/plasmacytoid DCs (pDCs), respectively. CD8SP thymocytes indirectly support pDC survival and cDC2 thymic migration, and they induce interferon signaling in cDCs, partly by promoting type 3 interferon expression by medullary thymic epithelial cells. By contrast, CD4SP thymocytes undergo cognate interactions with cDCs, inducing CD40 signaling required for activation of cDC1s. Activated cDC1s make nonredundant contributions to central tolerance. Together, this study comprehensively identifies distinct thymic DC subsets and elucidates requirements for cross-talk with thymocyte subsets that support their homeostasis, activation and function.
Haku Y, Kitaoka K, Ichimaru K
… +18 more, Hirano T, Wang J, Sonomura K, Maruo A, Hirose S, Wang Y, Ito K, Kozuki T, Yurimoto K, Kiyono M, Kosako H, Menju T, Date H, Kobayashi T, Omori K, Yaguchi T, Honjo T, Chamoto K
Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8 T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Her...Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8 T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8 T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8 T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.