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The role of T cells in the resolution or exacerbation of COVID-19, as well as their potential to provide long-term protection from reinfection with SARS-CoV-2, remains debated. Nevertheless, recent studies have highlighted various aspects of T cell responses to SARS-CoV-2 infection that are starting to enable some general concepts to emerge.In this Progress article, Zeyu Chen and E. John Wherry summarize early reports of the T cell responses observed in patients with COVID-19, emphasizing how different immune response characteristics in different patients may reflect a spectrum of disease phenotypes.

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response.

Progenitor-like CD8 + T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8 + T cells responding to acute and chronic viral infections, we found that progenitor-like CD8 + T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8 + T cells and was required for the programming of progenitor-like CD8 + T cells. Thus, long-term CD8 + T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX. Long-lived, self-renewing ‘progenitor-like’ CD8 + T cells can arise during chronic viral infection or in cancer. Wu and colleagues identify the transcription factor TOX as essential to endow ‘stemness’ and long-term persistence in the face of chronic infection.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy ( n  = 20) compared with healthy controls ( n  = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (T FH ) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (T H 1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating T FH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20. SARS-CoV-2-specific antibodies and memory B cells are significantly reduced, but CD4 + and CD8 + T cells are robustly activated, in patients with multiple sclerosis on anti-CD20 monotherapy versus healthy controls after BNT162b2 or mRNA-1273 mRNA vaccination.

Pseudotime analysis with single-cell RNA-sequencing (scRNA-seq) data has been widely used to study dynamic gene regulatory programs along continuous biological processes. While many methods have been developed to infer the pseudotemporal trajectories of cells within a biological sample, it remains a challenge to compare pseudotemporal patterns with multiple samples (or replicates) across different experimental conditions. Here, we introduce Lamian, a comprehensive and statistically-rigorous computational framework for differential multi-sample pseudotime analysis. Lamian can be used to identify changes in a biological process associated with sample covariates, such as different biological conditions while adjusting for batch effects, and to detect changes in gene expression, cell density, and topology of a pseudotemporal trajectory. Unlike existing methods that ignore sample variability, Lamian draws statistical inference after accounting for cross-sample variability and hence substantially reduces sample-specific false discoveries that are not generalizable to new samples. Using both real scRNA-seq and simulation data, including an analysis of differential immune response programs between COVID-19 patients with different disease severity levels, we demonstrate the advantages of Lamian in decoding cellular gene expression programs in continuous biological processes. Pseudotime analysis is prevalent in single-cell RNA-seq, but it remains challenging to perform it across multiple samples and experimental conditions. Here, the authors develop Lamian, a computational framework for multi-sample pseudotime analysis that adjusts for biological and technical variation to detect gene program changes along cell trajectories and across conditions.

Exhausted CD8 T cells (T EX ) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate T EX cells, but reinvigoration is not durable. A major unanswered question is whether T EX cells differentiate into functional durable memory T cells (T MEM ) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, T EX cells partially (re)acquire phenotypic and transcriptional features of T MEM cells. These ‘recovering’ T EX cells originated from the T cell factor (TCF-1 + ) T EX progenitor subset. Nevertheless, the recall capacity of these recovering T EX cells remained compromised as compared to T MEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for T EX cell–targeted immunotherapies. Wherry and colleagues examine whether exhausted T cells (T EX ) can differentiate into functional memory T cells (T MEM ) when chronic antigen is withdrawn. Using the chronic LCMV infection mouse model, they show that ‘recovering’ T EX cells (REC-T EX ) only partially recover immunophenotypic and functional characteristics of T MEM cells. The epigenomic status of REC-T EX cells more closely resembles that of T EX cells, and, upon rechallenge, the REC-T EX cells were still compromised in their ability to respond to virus.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses. A study of hospitalized patients infected with SARS-CoV-2 and who have liquid or solid cancer suggests that hematologic malignancy is an independent risk factor for mortality and that CD8 + T cells might limit infection in this setting irrespective of humoral immunity.

During chronic infection and cancer, a self-renewing CD8 + T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8 + T cells diverge from other CD8 + subsets early after chronic viral infection. However, pathways guarding stem-like CD8 + T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8 + T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8 + T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8 + T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8 + lineage and prevents an alternative terminally exhausted cell fate. Tuoqi Wu and colleagues show that the transcriptional repressor BACH2 is required early after chronic viral infection to enforce a stem-like fate in activated CD8 + T cells. BACH2 acts to suppress genes that lead to the exhausted cell state.

The mammalian intestine is colonized by beneficial commensal bacteria and is a site of infection by pathogens, including helminth parasites. Helminths induce potent immunomodulatory effects, but whether these effects are mediated by direct regulation of host immunity or indirectly through eliciting changes in the microbiota is unknown. We tested this in the context of virus-helminth coinfection. Helminth coinfection resulted in impaired antiviral immunity and was associated with changes in the microbiota and STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule that is associated with alternatively activated macrophages, could partially restore antiviral immunity. These data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.

In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.