T cell exhaustion is common during chronic infections. Although CD4+ T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and ...transcriptional program. We defined the phenotypic, functional, and molecular profiles of exhausted CD4+ T cells. Global transcriptional analysis demonstrated a molecular profile distinct from effector and memory CD4+ T cells and also from exhausted CD8+ T cells, though some common features of CD4+ and CD8+ T cell exhaustion were revealed. We have demonstrated unappreciated roles for transcription factors (TFs) including Helios, type I interferon (IFN-I) signaling, and a diverse set of coinhibitory and costimulatory molecules during CD4+ T cell exhaustion. Moreover, the signature of CD4+ T cell exhaustion was found to be distinct from that of other CD4+ T cell lineage subsets and was associated with TF heterogeneity. This study provides a framework for therapeutic interventions targeting exhausted CD4+ T cells.
•Exhausted CD4+ T cells have a distinct molecular profile•Exhausted CD4+ and CD8+ T cells have a diverse inhibitory receptor profiles•A unique transcription factor signature is associated with CD4+ T cell exhaustion•The molecular profile of exhausted CD4+ T cells is distinct from other Th cell subsets
Costimulatory and inhibitory receptors are critical regulators of adaptive immune cell function. These pathways regulate the initiation and termination of effective immune responses to infections ...while limiting autoimmunity and/or immunopathology. This review focuses on recent advances in our understanding of inhibitory receptor pathways and their roles in different diseases and/or infections, emphasizing potential clinical applications and important unanswered mechanistic questions. Although significant progress has been made in defining the influence of inhibitory receptors at the cellular level, relatively little is known about the underlying molecular pathways. We discuss our current understanding of the molecular mechanisms for key inhibitory receptor pathways, highlight major gaps in knowledge, and explore current and future clinical applications.
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about ...mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T ...cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.
Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8+ T (Tex) cells is poorly understood. We ...found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8+ T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.
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•Early exhausted T cells exhibit repressed glycolytic and mitochondrial metabolism•Metabolic skewing occurred despite mTOR-driven upregulation of anabolic pathways•PD-1 regulated bioenergetic insufficiencies early and late in infection•PGC-1α overexpression improved metabolism and T cell function
Exhausted T cells progressively develop poor effector function in chronic infections and cancer and are a barrier to controlling these diseases. Wherry and colleagues identify suppressed T cell metabolism as an early cellular perturbation driving exhaustion and implicate PD-1 and altered glycolytic, mitochondrial, and PGC-1α-driven metabolic pathways in the process.
Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 Tcells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable ...memory Tcells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector Tcells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
Chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling this regenerative ...capacity, however, are unknown. We found that two distinct states of virus-specific CD8⁺ T cells exist in chronically infected mice and humans. Differential expression of the T-box transcription factors T-bet and Eomesodermin (Eomes) facilitated the cooperative maintenance of the pool of antiviral CD8⁺ T cells during chronic viral infection. T-bet hi cells displayed low intrinsic turnover but proliferated in response to persisting antigen, giving rise to Eomes hi terminal progeny. Genetic elimination of either subset resulted in failure to control chronic infection, which suggests that an imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections.
An Interferon Paradox Odorizzi, Pamela M.; Wherry, E. John
Science,
04/2013, Volume:
340, Issue:
6129
Journal Article
Peer reviewed
Open access
Interferons must balance antiviral actions against immunosuppressive effects during acute and chronic infections.
Also see Reports by
Wilson
et al.
and
Teijaro
et al.
Type 1 interferons (IFN-α/β) ...are a major first line of host defense against viral infection. Because of this potent antiviral activity, IFN-based therapies have been developed for chronic infections with hepatitis B and C viruses, as well as for HIV. However, a poorly understood phenomenon has been the persistence of virus despite induction of antiviral immune responses by type 1 IFNs. On page 207 and 202 in this issue, Teijaro
et al.
(
1
) and Wilson
et al.
(
2
) address this long-standing question and find that IFN-α/β can also suppress the immune system in ways that promote viral persistence. This paradoxical finding should spur a reassessment of the fundamental roles of IFN-α/β during chronic infections.
The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are ...needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients.
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•Early loss of PD-1 leads to overactivation of CD8+ T cells during acute infection•Mice constitutively lacking PD-1 or PD-L develop impaired CD8+ T cell memory•Cell-intrinsic PD-1 signals suppress effector cell expansion and promote memory•Timing of PD-1 blockade determines impact on memory generation
The role of PD-1 in memory development is poorly understood. Here, Pauken et al. show that constitutive loss of PD-1 during acute infection causes overactivation of CD8+ T cells during the effector phase and impairs memory and recall responses. These data indicate PD-1 is required for optimal memory.
The transcription factor BATF is required for the differentiation of interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and follicular helper T cells (TFH cells). Here we identified a ...fundamental role for BATF in regulating the differentiation of effector of CD8(+) T cells. BATF-deficient CD8(+) T cells showed profound defects in effector population expansion and underwent proliferative and metabolic catastrophe early after encountering antigen. BATF, together with the transcription factors IRF4 and Jun proteins, bound to and promoted early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies T cell antigen receptor (TCR)-dependent expression of transcription factors and augments the propagation of inflammatory signals but restrains the expression of genes encoding effector molecules. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved.
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