Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and ...-extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 75% of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.
The molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly ...understood. We have utilized ChIP-seq to assess histone H3 methylation dynamics within naive, effector, and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naive T cells, codeposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication, and cellular differentiation. Upon differentiation into effector and/or memory CTLs, the majority of these gene loci lose repressive H3K27me3 while retaining the permissive H3K4me3 modification. In contrast, immune-related effector gene promoters within naive T cells lacked the permissive H3K4me3 modification, with acquisition of this modification occurring upon differentiation into effector/memory CTLs. Thus, coordinate transcriptional regulation of CTL genes with related functions is achieved via distinct epigenetic mechanisms.
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•Specific H3K4me3 and H3K27me3 patterns identify functionally related CTL genes•Many CTL-specific transcription factors are bivalent for H3K4me3 and H3K27me3•Bivalent loci largely resolve to a permissive signature rapidly after activation•H3K4me2 identifies a subset of rapidly transcribed immune-specific gene loci
It is unclear how changes in genome-wide histone methylation status regulate distinct transcriptional signatures observed in naive, effector, and memory virus-specific cytotoxic lymphocytes. Russ et al. identify key epigenetic signatures that delineate distinct transcriptional programs that underpin CD8+ T cell differentiation during infection.
Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully ...exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.
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•Post-effector de novo DNA methylation programs promote terminal T cell exhaustion•Exhaustion-associated DNA methylation programs are preserved during PD-1 blockade•Blocking de novo methylation enhances PD-1 blockade-mediated T cell rejuvenation•PD-1hi TILs acquire exhaustion-associated DNA-methylation programs
De novo DNA methylation programs promote T cell exhaustion, and inhibiting these programs can enhance immune-checkpoint-blockade-mediated T cell rejuventation and ultimately facilitate the control of chronic viral infections and tumor growth.
It is currently thought that T cells with specificity for self-peptide/MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4+ T cells, what is ...unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3+ regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4+ T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3– cells, but also contained a subset of Foxp3+ regulatory cells. Both Foxp3– and Foxp3+ pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3+ subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII–specific CD4+ T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.
Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7
CD45RA
effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.
Analysis of pre-existing immunity and its effects on acute infection often focus on memory responses associated with a prior infectious exposure. However, memory responses occur in the context of the ...overall immune state and leukocytes must interact with their microenvironment and other immune cells. Thus, it is important to also consider non-antigen-specific factors which shape the composite basal state and functional capacity of the immune system, termed here as I
('I naught'). In this review, we discuss the determinants of I
. Utilizing influenza virus as a model, we then consider the effect of I
on susceptibility to infection and disease severity. Lastly, we outline a mathematical framework and demonstrate how researchers can build and tailor models to specific needs. Understanding how diverse factors uniquely and collectively impact immune competence will provide valuable insights into mechanisms of immune variation, aid in screening for high-risk populations, and promote the development of broadly applicable prophylactic and therapeutic treatments.
The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the ...respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.
Thomas and colleagues present an overview of pulmonary immunity, covering innate and adaptive responses following infection and vaccination, with a particular focus on responses to influenza and SARS-CoV-2. They also highlight exciting recent advances and the importance of continuing research efforts into human respiratory health.
Postnatal depression in women is associated with adverse effects on both maternal health and children's development. It is unclear whether depression in men at this time poses comparable risks. The ...present study set out to assess the association between depression in men in the postnatal period and later psychiatric disorders in their children and to investigate predisposing factors for depression in men following childbirth.
A population-based cohort of 10,975 fathers and their children from the Avon Longitudinal Study of Parents and Children (ALSPAC) was recruited in the prenatal period and followed for 7 years. Paternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale and later child psychiatric disorder (DSM-IV) with the Development and Well-Being Assessment.
Depression in fathers in the postnatal period was significantly associated with psychiatric disorder in their children 7 years later (adjusted OR 1.72, 95% CI 1.07-2.77), most notably oppositional defiant/conduct disorders (adjusted OR 1.94, 95% CI 1.04-3.61), after adjusting for maternal depression and paternal educational level. A history of severe depression and high prenatal symptom scores for depression and anxiety were the strongest predictors of paternal depression in the postnatal period.
Depression in fathers in the postnatal period is associated with later psychiatric disorders in their children, independently of maternal postnatal depression. Further research into the risks associated with paternal psychopathology is required because this could represent an important opportunity for public health intervention.
The successes of antitumor immuno-based therapies and the application of next-generation sequencing to mutation profiling have produced insights into the specific targets of antitumor T cells. ...Mutated proteins have tremendous potential as targets for interventions using autologous T cells or engineered cell therapies and may serve as important correlates of efficacy for immunoregulatory interventions including immune checkpoint blockade. As mutated self, tumors present an exceptional case for host immunity, which has primarily evolved in response to foreign pathogens. Tumor Ags' resemblance to self may limit immune recognition, but key features appear to be the same between antipathogen and antitumor responses. Determining which targets will make efficacious Ags and which responses might be elicited therapeutically are key questions for the field. Here we discuss current knowledge on antitumor specificity, the mutations that provide immunogenic targets, and how cross-reactivity and immunodominance may contribute to variation in immune responses among tumor types.
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