Congruent visual speech improves speech perception accuracy, particularly in noisy environments. Conversely, mismatched visual speech can alter what is heard, leading to an illusory percept that differs from the auditory and visual components, known as the McGurk effect. While prior transcranial magnetic stimulation (TMS) and neuroimaging studies have identified the left posterior superior temporal sulcus (pSTS) as a causal region involved in the generation of the McGurk effect, it remains unclear whether this region is critical only for this illusion or also for the more general benefits of congruent visual speech (e.g., increased accuracy and faster reaction times). Indeed, recent correlative research suggests that the benefits of congruent visual speech and the McGurk effect rely on largely independent mechanisms. To better understand how these different features of audiovisual integration are causally generated by the left pSTS, we used single-pulse TMS to temporarily disrupt processing within this region while subjects were presented with either congruent or incongruent (McGurk) audiovisual combinations. Consistent with past research, we observed that TMS to the left pSTS reduced the strength of the McGurk effect. Importantly, however, left pSTS stimulation had no effect on the positive benefits of congruent audiovisual speech (increased accuracy and faster reaction times), demonstrating a causal dissociation between the two processes. Our results are consistent with models proposing that the pSTS is but one of multiple critical areas supporting audiovisual speech interactions. Moreover, these data add to a growing body of evidence suggesting that the McGurk effect is an imperfect surrogate measure for more general and ecologically valid audiovisual speech behaviors.

Abstract BACKGROUND We recently demonstrated that glioma-infiltrated cortex engages in task-specific computations but may encode less information while doing so. The mechanistic underpinnings of glioma burden and its behavioral impact remains unknown OBJECTIVE To investigate the relationship between glioma burden and degree of cognitive impairments. METHODS One-hundred-eight patients with newly diagnosed WHO 2-4 diffuse glioma were recruited from a UCSF prospective registry. MRI FLAIR and T1 post-gadolinium tumor volume masks were demarcated. A “Composite” mask was generated from the sum of T1 post-gadolinium and FLAIR volume masks. Participants completed language assessments using the Quick Aphasia Battery (QAB). Glioma burden was determined by tumor-specific marker expression (IDH-1 mutation and P53) and glioma proliferation (Ki-67 and MIB-1 proliferation index). For each mask type, support-vector regression voxel-lesion symptom mapping (SVR-LSM) and linear regression analyses were performed to identify anatomic regions of interest (ROI) and glioma-specific factors associated with lower QAB scores. RESULTS SVR-LSM analysis by mask type revealed significant clusters in the left superior temporal gyrus: composite lesions within a cluster of 41,762 voxels and T1 post-gadolinium lesions within a cluster of 42,570 voxels. Both were independently predictive of lower QAB scores. SVR-LSM analysis of FLAIR masks failed to produce any significant clusters. Multivariate linear regression analysis of composite lesions was utilized to control for composite lesion voxel volume, glioma grade, and tumor-specific marker expression. The presence of voxels overlapping with the composite lesion ROI scores (beta = -0.13; p < 0.001), and, relative to a low glioma proliferation group (< 2%), glioma proliferation between 31-50% (beta = -2.00, p = 0.044) were independently and significantly predictive of lower QAB scores. CONCLUSION Relative to a low glioma proliferation group (< 2%), glioma proliferation between 31-50% significantly predicts language impairments, with a linear relationship between voxel overlap with ROI and impairment severity.

Immune checkpoint blockade targeting PD-1 shows great success in cancer therapy. However, the mechanism of how ligand binding initiates PD-1 signaling remains unclear. As prognosis markers of multiple cancers, soluble PD-L1 is found in patient sera and can bind PD-1, but fails to suppress T cell function. This and our previous observations that T cells exert endogenous forces on PD-1-PD-L2 bonds prompt the hypothesis that mechanical force might be critical to PD-1 triggering, which is missing in the soluble ligand case due to the lack of mechanical support afforded by surface-anchored ligand. Here we show that PD-1 function is eliminated or reduced when mechanical support on ligand is removed or dampened, respectively. Force spectroscopic analysis reveals that PD-1 forms catch bonds with both PD-Ligands <7 pN where force prolongs bond lifetime, but slip bonds >8 pN where force accelerates dissociation. Steered molecular dynamics finds PD-1-PD-L2 complex very sensitive to force due to the two molecules' "side-to-side" binding via β sheets. Pulling causes relative rotation and translation between the two molecules by stretching and aligning the complex along the force direction, yielding new atomic contacts not observed in the crystal structure. Compared to wild-type, PD-1 mutants targeting the force-induced new interactions maintain the same binding affinity but display lower rupture force, shorter bond lifetime, reduced tension, and most importantly, impaired capacity to suppress T cell activation. Our results uncover a mechanism for cells to probe the mechanical support of PD-1-PD-Ligand bonds using endogenous forces to regulate PD-1 triggering.

Sounds enhance our ability to detect, localize, and respond to co-occurring visual targets. Research suggests that sounds improve visual processing by resetting the phase of ongoing oscillations in visual cortex. However, it remains unclear what information is relayed from the auditory system to visual areas and if sounds modulate visual activity even in the absence of visual stimuli (e.g., during passive listening). Using intracranial electroencephalography (iEEG) in humans, we examined the sensitivity of visual cortex to three forms of auditory information during a passive listening task: auditory onset responses, auditory offset responses, and rhythmic entrainment to sounds. Because some auditory neurons respond to both sound onsets and offsets, visual timing and duration processing may benefit from each. In addition, if auditory entrainment information is relayed to visual cortex, it could support the processing of complex stimulus dynamics that are aligned between auditory and visual stimuli. Results demonstrate that in visual cortex, amplitude-modulated sounds elicited transient onset and offset responses in multiple areas, but no entrainment to sound modulation frequencies. These findings suggest that activity in visual cortex (as measured with iEEG in response to auditory stimuli) may not be affected by temporally fine-grained auditory stimulus dynamics during passive listening (though it remains possible that this signal may be observable with simultaneous auditory-visual stimuli). Moreover, auditory responses were maximal in low-level visual cortex, potentially implicating a direct pathway for rapid interactions between auditory and visual cortices. This mechanism may facilitate perception by time-locking visual computations to environmental events marked by auditory discontinuities.NEW & NOTEWORTHY Using intracranial electroencephalography (iEEG) in humans during a passive listening task, we demonstrate that sounds modulate activity in visual cortex at both the onset and offset of sounds, which likely supports visual timing and duration processing. However, more complex auditory rate information did not affect visual activity. These findings are based on one of the largest multisensory iEEG studies to date and reveal the type of information transmitted between auditory and visual regions.

CD8 T cells play a critical role in viral immunity and it is important to understand how memory cells are formed and what processes lead to their long-term maintenance. Here, we use a mouse model of acute infection to perform an in-depth, longitudinal analysis of memory CD8 T cell differentiation, examining the phenotype and location of memory cells out to 1 year postinfection.

Objectives Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms. Methods In this study, we used continuous video-electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)-in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals. Results To the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data. Significance Together, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.

OBJECTIVE Intraoperative tasks for awake language mapping are typically selected based on the language tracts that will likely be encountered during tumor resection. However, diminished attention and arousal secondary to perioperative sedatives may reduce a task's usefulness for identifying eloquent cortex. For instance, accuracy in performing select language tasks may be high preoperatively but decline in the operating room. In the present study, the authors sought to identify language tasks that can be performed with high accuracy in both situational contexts so the neurosurgical team can be confident that speech errors committed during awake language mapping result from direct cortical stimulation to eloquent cortex, rather than from poor performance in general. METHODS We administered five language tasks to 44 patients: picture naming (PN), text reading (TR), auditory object naming (AN), repetition of 4-syllable words (4SYL), and production of syntactically intact sentences (SYNTAX). Performance was assessed using the 4-point scale of the quick aphasia battery 24 hours preoperatively and intraoperatively. We next determined whether or not accuracy on each task was higher preoperatively than intraoperatively. We also determined whether 1) intraoperative accuracy on a given task predicted intraoperative performance on the other tasks and 2) low preoperative accuracy on a task predicted a decrease in accuracy intraoperatively. RESULTS Relative to preoperative accuracy, intraoperative accuracy declined on PN (3.90 vs 3.82, p = 0.0001), 4SYL (3.96 vs 3.91, p = 0.0006), and SYNTAX (3.85 vs 3.67, p = 0.0001) but not on TR (3.96 vs 3.94, p = 0.13) or AN (3.70 vs 3.58, p = 0.058). Intraoperative accuracy on PN and AN independently predicted intraoperative accuracy on the remaining language tasks (p < 0.001 and p < 0.01, respectively). Finally, low preoperative accuracy on SYNTAX predicted a decrease in accuracy on this task intraoperatively (R2 = 0.36, p = 0.00002). CONCLUSIONS While TR lacks sensitivity in identifying language deficits at baseline, accuracy on TR is stable across testing settings. Baseline accuracy on the other four of our five language tasks was not predictive of intraoperative performance, signifying the need to repeat language tests prior to stimulation mapping to confirm reliability.

Despite the clinical success of blocking its interactions, how PD-1 inhibits T-cell activation is incompletely understood, as exemplified by its potency far exceeding what might be predicted from its affinity for PD-1 ligand-1 (PD-L1). This may be partially attributed to PD-1’s targeting the proximal signaling of the T-cell receptor (TCR) and co-stimulatory receptor CD28 via activating Src homology region 2 domain-containing phosphatases (SHPs). Here, we report PD-1 signaling regulates the initial TCR antigen recognition manifested in a smaller spreading area, fewer molecular bonds formed, and shorter bond lifetime of T cell interaction with peptide-major histocompatibility complex (pMHC) in the presence than absence of PD-L1 in a manner dependent on SHPs and Leukocyte C-terminal Src kinase. Our results identify a PD-1 inhibitory mechanism that disrupts the cooperative TCR–pMHC–CD8 trimolecular interaction, which prevents CD8 from augmenting antigen recognition, explaining PD-1’s potent inhibitory function and its value as a target for clinical intervention.

OBJECTIVE Maximal safe tumor resection in language areas of the brain relies on a patient's ability to perform intraoperative language tasks. Assessing the performance of these tasks during awake craniotomies allows the neurosurgeon to identify and preserve brain regions that are critical for language processing. However, receiving sedation and analgesia just prior to experiencing an awake craniotomy may reduce a patient's wakefulness, leading to transient language and/or cognitive impairments that do not completely subside before language testing begins. At present, the degree to which wakefulness influences intraoperative language task performance is unclear. Therefore, the authors sought to determine whether any of 5 brief measures of wakefulness predicts such performance during awake craniotomies for glioma resection. METHODS The authors recruited 21 patients with dominant hemisphere low- and high-grade gliomas. Each patient performed baseline wakefulness measures in addition to picture- naming and text-reading language tasks 24 hours before undergoing an awake craniotomy. The patients performed these same tasks again in the operating room following the cessation of anesthesia medications. The authors then conducted statistical analyses to investigate potential relationships between wakefulness measures and language task performance. RESULTS Relative to baseline, performance on 3 of the 4 objective wakefulness measures (rapid counting, button pressing, and vigilance) declined in the operating room. Moreover, these declines appeared in the complete absence of self-reported changes in arousal. Performance on language tasks similarly declined in the intraoperative setting, with patients experiencing greater declines in picture naming than in text reading. Finally, performance declines on rapid counting and vigilance wakefulness tasks predicted performance declines on the picture-naming task. CONCLUSIONS Current subjective methods for assessing wakefulness during awake craniotomies may be insufficient. The administration of objective measures of wakefulness just prior to language task administration may help to ensure that patients are ready for testing. It may also allow neurosurgeons to identify patients who are at risk for poor intraoperative performance.

Lck-interacting transmembrane adaptor 1 (LIME) has been previously identified as a raft-associated transmembrane protein expressed predominantly in T and B lymphocytes. Although LIME is shown to transduce the immunoreceptor signaling and immunological synapse formation via its tyrosine phosphorylation by Lck, a Src-family kinase, the in vivo function of LIME has remained elusive in the previous studies. Here we report that LIME is preferentially expressed in effector T cells and mediates chemokine-mediated T cell migration. Interestingly, in LIME-/- mice, while T cell receptor stimulation-dependent proliferation, differentiation to effector T cells, cytotoxic T lymphocyte (CTL) function and regulatory T lymphocyte (Treg) function were normal, only T cell-mediated inflammatory response was significantly defective. The reduced inflammation was accompanied by the impaired infiltration of leukocytes and T cells to the inflammatory sites of LIME-/- mice. More specifically, the absence of LIME in effector T cells resulted in the reduced migration and defective morphological polarization in response to inflammatory chemokines such as CCL5 and CXCL10. Consistently, LIME-/- effector T cells were found to be defective in chemokine-mediated activation of Rac1 and Rap1, and dysregulated phosphorylation of Pyk2 and Cas. Taken together, the present findings show that LIME is a critical regulator of inflammatory chemokine-mediated signaling and the subsequent migration of effector T cells to inflammatory sites.

Synesthesia is an atypical perceptual phenomenon that has been associated with generalized differences in other cognitive and perceptual domains. Given similarities in the qualitative nature of synesthetic experiences to visual imagery perceptions, several studies have sought to examine whether synesthetes demonstrate increased visual imagery abilities. Using subjective imagery questionnaires, some studies have identified superior imaging abilities in synesthetes, while others have not. However, because most research on synesthesia uses un-blinded group membership prior to data collection, such methods for studying group differences may be prone to participant and experimenter biases (e.g., a motivated synesthete may rate themselves as having stronger visual imagery abilities due to their own bias and perceived experimenter expectations). To address this issue, we demonstrate the feasibility of double-blind designs in synesthesia research, applied here to examine differences in subjectively reported levels of imagery usage and intensity. Prior to identifying synesthetes' and non-synesthetes' group membership (in order to eliminate the potential for bias), subjects completed two common measures of visual imagery experiences. Using this approach, we replicated findings of greater visual imagery usage in synesthetes on the Spontaneous Use of Imagery Scale (SUIS) measure, but not of enhanced imagery abilities on the standardized Vividness of Visual Imagery Questionnaire (VVIQ) measure. The present study strengthens prior evidence that synesthesia is associated with heightened visual imagery and demonstrates the utility of double-blind designs in order to limit biases and promote further replicability of other findings in research on synesthesia.

Sounds enhance visual cortical sensitivity for co-occurring visual signals. Previous research has demonstrated that this facilitation occurs through crossmodal modulations of cortical oscillatory activity. However, the neural origin of these signals and auditory information conveyed by this mechanism remain poorly understood. Using intracranial electroencephalography (iEEG) in humans, we examined the sensitivity of visual cortex to three different forms of auditory information: rhythmic entrainment to sounds, auditory onset responses, and auditory offset responses. Subcortical auditory neurons exhibit frequency following behaviors in response to amplitude-modulated sounds, with oscillatory activity entrained at the rhythmic rate of the auditory signal. This auditory response is paralleled in the visual system by the entrainment of visual neurons to the rhythmic rate of flashing strobe lights. In contrast, ~20% of neurons in auditory cortex do not entrain to amplitude modulations but respond only to the onsets and/or offsets of auditory stimuli. In visual cortex, amplitude-modulated sounds elicited transient onset and offset responses in multiple areas, but no entrainment to the sounds’ modulations frequencies. These results suggest that auditory information conveyed to visual cortex does not include temporally fine-grained stimulus dynamics encoded by the auditory midbrain and thalamus but, rather, a temporally segmented representation of auditory events that emerges only in auditory cortex. Crossmodal responses were maximal in low-level visual cortex, potentially implicating a direct pathway for rapid interactions between low-to-mid-level auditory and visual cortices. This mechanism may facilitate perception by time-locking visual computations to environmental events marked by discontinuities in auditory input.

Co-occurring sounds can facilitate perception of spatially and temporally correspondent visual events. Separate lines of research have identified two putatively distinct neural mechanisms underlying two types of crossmodal facilitations: Whereas crossmodal phase resetting is thought to underlie enhancements based on temporal correspondences, lateralized occipital evoked potentials (ERPs) are thought to reflect enhancements based on spatial correspondences. Here, we sought to clarify the relationship between these two effects to assess whether they reflect two distinct mechanisms or, rather, two facets of the same underlying process. To identify the neural generators of each effect, we examined crossmodal responses to lateralized sounds in visually responsive cortex of 22 patients using electrocorticographic recordings. Auditory-driven phase reset and ERP responses in visual cortex displayed similar topography, revealing significant activity in pericalcarine, inferior occipital-temporal, and posterior parietal cortex, with maximal activity in lateral occipitotemporal cortex (potentially V5/hMT+). Laterality effects showed similar but less widespread topography. To test whether lateralized and nonlateralized components of crossmodal ERPs emerged from common or distinct neural generators, we compared responses throughout visual cortex. Visual electrodes responded to both contralateral and ipsilateral sounds with a contralateral bias, suggesting that previously observed laterality effects do not emerge from a distinct neural generator but rather reflect laterality-biased responses in the same neural populations that produce phase-resetting responses. These results suggest that crossmodal phase reset and ERP responses previously found to reflect spatial and temporal facilitation in visual cortex may reflect the same underlying mechanism. We propose a new unified model to account for these and previous results.

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti-PD-L1 or anti-PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

DNA methylation profiling of virus-specific T cells during acute viral infection in mice provides evidence that a fate-permissive subset of effector CD8 T cells dedifferentiates into long-lived memory T cells. Memory cells protect against reinfection, or protect against infection after vaccination, but whether they are derived from naive or effector T cells is unknown. Rafi Ahmed and colleagues study the generation, maintenance and characteristics of long-lived memory CD8 T cells in humans after yellow fever vaccination and deuterium labelling. The study demonstrates that long-lived memory CD8 T cells are derived from cells that have divided extensively during the effector phase of the infection. Quiescent memory cells appear to revert to a naive phenotype but maintain an upregulated pattern of gene regulation that resembles effector T cells. In a second paper in this issue, Rafi Ahmed and colleagues examine changes in DNA methylation during effector and memory CD8 T cell differentiation, providing support for a model in which long-lived memory cells arise from a precursor of effector cells. Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells1,2,3,4. Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation. To assess the developmental origin of memory CD8 T cells, we investigated changes in DNA methylation programming at naive and effector cell-associated genes in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection in mice. Methylation profiling of terminal effector versus memory-precursor CD8 T cell subsets showed that, rather than retaining a naive epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naive-associated genes and became demethylated at the loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells. Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naive-associated genes. Thus, epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fate-permissive effector T cells.

ABSTRACT PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection. We observed that LCMV-specific CD8 T cells from chronically infected mice maintained their surface expression of PD-1 even after transfer into acute immune mice until day 45 posttransfer. Interestingly, the PD-1 transcriptional regulatory region continued to remain unmethylated in these donor CD8 T cells generated from a chronic infection. The observed maintenance of PD-1 surface expression and the demethylated PD-1 promoter were not a result of residual antigen in the recipient mice, because similar results were seen when chronic infection-induced effector cells were transferred into mice infected with a variant strain of LCMV (LCMV V35A) bearing a mutation in the cognate major histocompatibility complex class I (MHC-I) epitope that is recognized by the donor CD8 T cells. Importantly, the maintenance of PD-1 promoter demethylation in memory CD8 T cells was coupled with impaired clonal expansion and higher PD-1 re-expression upon secondary challenge. These data show that the imprinting of the epigenetic program of the inhibitory receptor PD-1 occurs during the effector phase of chronic viral infection. IMPORTANCE Since PD-1 is a major inhibitory receptor regulating T cell dysfunction during chronic viral infection and cancers, a better understanding of the mechanisms that regulate PD-1 expression is important. In this work, we demonstrate that the PD-1 epigenetic program in antigen-specific CD8 T cells is fixed during the priming phase of chronic infection.

Antigen-specific CD8 T cells play a critical role in controlling chronic infections and cancer, but progressively lose their effector functions during prolonged antigen exposure. Repression of CD8 T cell effector functions, commonly referred to as T cell exhaustion, limits the ability of the immune system to purge the chronic pathogen from the host. It has recently become recognized that CD8 T cell exhaustion programs can be reinforced and heritably maintained. Therefore in order to develop and/or improve current therapeutic approaches that utilize host antigen-specific T cells to treat chronic infections or cancer a major challenge for the field is to identify mechanisms that stabilize T cell exhaustion. We have recently found that epigenetic modifications acquired in pathogen-specific CD8 T cells during prolonged antigen exposure reinforce T cell exhaustion. Using the LCMV model system of chronic viral infection we investigated the role of Dnmt3a mediated de novo DNA methylation in regulating CD8 T cell exhaustion. Strikingly, conditional deletion of Dnmt3a in activated CD8 T cells blocked the cells from becoming exhausted. Longitudinal analysis of whole-genome methylation programming of WT and Dnmt3a cKO CD8 T cells from chronically infected animals reveals progressive acquisition of Dnmt3a-dependent DNA methylation programs in genes, including interferon gamma, that are coupled to the progressive decline of effector functions. These results have significant implications for therapeutic strategies that utilize reactivation of host pathogen-specific CD8 T cells to control chronic viral infections or cancer and provide a nucleotide-resolution map of epigenetic programs progressively acquired during T cell exhaustion.

Virus-specific CD8 T cells play a critical role in controlling chronic infections such as HIV and HCV, but progressively lose their antiviral functions during prolonged antigen exposure. Repression of CD8 T cell effector functions, commonly referred to as T cell exhaustion, limits the ability of the immune system to purge viral reservoirs from the host. Therapies that transiently rejuvenate exhausted virus-specific CD8 T cells have been highly successful at recovering antiviral functions, but a current challenge for the field is to identify mechanisms for stably reprogramming exhausted CD8 T cells so that recovered antiviral properties can be long-lived. We have recently demonstrated that epigenetic modifications acquired in pathogen-specific CD8 T cells during prolonged antigen exposure (chronic viral infections) reinforces T cell exhaustion. Using a mouse model system of chronic viral infection we investigated the role of Dnmt3a mediated de novo DNA methylation in regulating CD8 T cell exhaustion. Strikingly, conditional deletion of Dnmt3a in activated CD8 T cells blocked the cells from becoming exhausted. Moreover, in the absence of acquiring a de novo exhaustion program, pathogen-specific CD8 T cells are able to control what normally is a chronic viral infection. These results have significant implications for therapeutic strategies that utilize reactivation of host pathogen-specific CD8 T cells to control chronic viral infections or cancer.

T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. Recently, antibodies blocking PD-1 have been approved for use in cancer patients. In this review, we summarize the role of the PD-1 pathway in chronic infection and cancer and the therapeutic potential of PD-1-directed immunotherapy in patients with chronic infection or cancer.