TET2 regulates early and late transitions in exhausted CD8 T cell differentiation and limits CAR T cell function.

CD8 T cell exhaustion hampers control of cancer and chronic infections and limits chimeric antigen receptor (CAR) T cell efficacy. Targeting in CAR T cells provides therapeutic benefit; however, TET2's role in exhausted T cell (T) development is unclear. In chronic lymphocytic choriomeningitis virus (LCMV) infection, TET2 drove conversion from stem cell-like T progenitors toward terminally differentiated and effector (T)-like T.

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy.

Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition.

Stat5 opposes the transcription factor Tox and rewires exhausted CD8 T cells toward durable effector-like states during chronic antigen exposure.

Rewiring exhausted CD8 T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Tex) to intermediate (Tex) and terminal (Tex) subsets, suggesting development flexibility.

CD8 T cells in the cancer-immunity cycle.

CD8 T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8 T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8 T cell subtypes and states.

Prior vaccination promotes early activation of memory T cells and enhances immune responses during SARS-CoV-2 breakthrough infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave.

In vitro modeling of CD8 T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40.

Identifying molecular mechanisms of exhausted CD8 T cells (T) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T can be costly and inefficient. In vitro models of T are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays.

The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR CD8 effector state, and its deletion improves checkpoint blockade.

CD8 T cell exhaustion (T) impairs the ability of T cells to clear chronic infection or cancer. While T are hypofunctional, some T retain effector gene signatures, a feature associated with killer lectin-like receptor (KLR) expression. Although KLR T (T) may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood.

The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8 T cells.

CD8 T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation.

Modeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40.

Identifying novel molecular mechanisms of exhausted CD8 T cells (T ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of T can be costly and inefficient. models of T are easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays.

The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR CD8 effector state and its deletion improves checkpoint blockade.

T cell exhaustion (T ) impairs the ability of T cells to clear chronic infection or cancer. While exhausted T cells are hypofunctional, some exhausted T cells retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR T cells may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood.

Prior vaccination enhances immune responses during SARS-CoV-2 breakthrough infection with early activation of memory T cells followed by production of potent neutralizing antibodies.

SARS-CoV-2 infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave.

Divergent clonal differentiation trajectories of T cell exhaustion.

Chronic antigen exposure during viral infection or cancer promotes an exhausted T cell (Tex) state with reduced effector function. However, whether all antigen-specific T cell clones follow the same Tex differentiation trajectory remains unclear. Here, we generate a single-cell multiomic atlas of T cell exhaustion in murine chronic viral infection that redefines Tex phenotypic diversity, including two late-stage Tex subsets with either a terminal exhaustion (Tex) or a killer cell lectin-like receptor-expressing cytotoxic (Tex) phenotype.

Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine.

We examined antibody and memory B cell responses longitudinally for ∼9-10 months after primary 2-dose SARS-CoV-2 mRNA vaccination and 3 months after a 3rd dose. Antibody decay stabilized between 6 and 9 months, and antibody quality continued to improve for at least 9 months after 2-dose vaccination. Spike- and RBD-specific memory B cells remained durable over time, and 40%-50% of RBD-specific memory B cells simultaneously bound the Alpha, Beta, Delta, and Omicron variants.

Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19.

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease.