PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis.

Background: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy.

PGE limits effector expansion of tumour-infiltrating stem-like CD8 T cells.

Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1CD8 T cell-mediated anticancer immunity.

B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP4. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood.

A distinct stimulatory cDC1 subpopulation amplifies CD8 T cell responses in tumors for protective anti-cancer immunity.

Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8 T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1 stem-like CD8 T cells.

Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses.

Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell responses within tumors, but it is poorly understood how this function is regulated and whether its subversion contributes to immune evasion. Here, we show that tumor-derived prostaglandin E2 (PGE) programmed a dysfunctional state in intratumoral cDC1s, disabling their ability to locally orchestrate anti-cancer CD8 T cell responses.

Unbiased chemokine receptor screening reveals similar efficacy of lymph node- and tumor-targeted T cell immunotherapy.

Localization is a crucial prerequisite for immune cell function and solid tumors evade immune control by modulating immune cell infiltration into the tumor stroma. Immunosuppressive cells like regulatory T cells are attracted, while cytotoxic CD8 T cells are excluded. Engineering CD8 T cells with chemokine receptors is a potent strategy to turn this mechanism of directed immune cell recruitment against the tumor.

Picking up speed: cell cycle regulation during effector CD8 T cell differentiation.

Clonal expansion and development of immunological memory are two hallmarks of adaptive immune responses. Resolving the intricate pathways that regulate cell cycle activity and lead to the generation of diverse effector and memory T cell subsets is essential for improving our understanding of protective T cell immunity. A deeper knowledge of cell cycle regulation in T cells also has translational implications for adoptive cell therapies and vaccinations against infectious diseases.

Recruitment of epitope-specific T cell clones with a low-avidity threshold supports efficacy against mutational escape upon re-infection.

Repetitive pathogen exposure leads to the dominant outgrowth of T cell clones with high T cell receptor (TCR) affinity to the relevant pathogen-associated antigens. However, low-affinity clones are also known to expand and form immunological memory. While these low-affinity clones contribute less immunity to the original pathogen, their role in protection against pathogens harboring immune escape mutations remains unclear.

Phosphatidylserine-positive extracellular vesicles boost effector CD8 T cell responses during viral infection.

CD8 T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine (PS) extracellular vesicles (EVs). These EVs interact especially with CD8 T cells; however, it remains unclear whether they can actively modulate CD8 T cell responses.

CagA-specific Gastric CD8 Tissue-Resident T Cells Control Helicobacter pylori During the Early Infection Phase.

Background & Aims: Infection with Helicobacter pylori strongly affects global health by causing chronic gastritis, ulcer disease, and gastric cancer. Although extensive research into the strong immune response against this persistently colonizing bacterium exists, the specific role of CD8 T cells remains elusive.

Methods: We comprehensively characterize gastric H pylori-specific CD8 T-cell responses in mice and humans by flow cytometry, RNA-sequencing, immunohistochemistry, and ChipCytometry, applying functional analyses including T-cell depletion, H pylori eradication, and ex vivo restimulation.

Single-cell fate mapping reveals widespread clonal ignorance of low-affinity T cells exposed to systemic infection.

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen-specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self-antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity.

Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity.

T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains challenging. Here, we investigated the fate and functionality of tumor neoantigen-specific T cells with TCRs of distinct avidities in a well-established, reductionist preclinical tumor model and human patients with melanoma.

Retrogenic Color-Barcoding for Fate Mapping of Single Innate Lymphocytes.

Lymphocyte fate mapping using single-cell transfers has been used to study T and B cell differentiation. Recently, retrogenic color-barcoding has allowed the extension of this approach to single innate lymphocytes such as NK cells. This new and versatile technology is based on the transduction of hematopoietic stem cells (HSCs) with a collection of retroviruses encoding distinct fluorescent proteins.

Heritable changes in division speed accompany the diversification of single T cell fate.

Rapid clonal expansion of antigen-specific T cells is a fundamental feature of adaptive immune responses. It enables the outgrowth of an individual T cell into thousands of clonal descendants that diversify into short-lived effectors and long-lived memory cells. Clonal expansion is thought to be programmed upon priming of a single naive T cell and then executed by homogenously fast divisions of all of its descendants.

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection.

Upon viral infection, natural killer (NK) cells expressing certain germline-encoded receptors are selected, expanded, and maintained in an adaptive-like manner. Currently, these are thought to differentiate along a common pathway. However, by fate mapping of single NK cells upon murine cytomegalovirus (MCMV) infection, we identified two distinct NK cell lineages that contributed to adaptive-like responses.

A Single-Cell Perspective on Memory T-Cell Differentiation.

Memory differentiation of CD4 and CD8 T-cell populations has been extensively studied and many key molecular players and transcriptional networks have been identified. But how regulatory principles, identified on this population level, translate to immune responses that originate from single antigen-specific T cells is only now being elucidated. Here, we provide a short summary of the approaches used for mapping the fate of individual T cells and their progeny in vivo.

Early emergence of T central memory precursors programs clonal dominance during chronic viral infection.

Chronic cytomegalovirus (CMV) infection leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called 'memory inflation' is thought to mainly depend on antigenic stimulation during the chronic phase of infection. However, by mapping the long-term development of CD8 T cell families derived from single naive precursors, we find that fate decisions made during the acute phase of murine CMV infection can alter the level of memory inflation by more than 1,000-fold.

Multiplexed whole-animal imaging with reversibly switchable optoacoustic proteins.

We introduce two photochromic proteins for cell-specific in vivo optoacoustic (OA) imaging with signal unmixing in the temporal domain. We show highly sensitive, multiplexed visualization of T lymphocytes, bacteria, and tumors in the mouse body and brain. We developed machine learning-based software for commercial imaging systems for temporal unmixed OA imaging, enabling its routine use in life sciences.

Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection.

Adaptive evolution is a key feature of T cell immunity. During acute immune responses, T cells harboring high-affinity T cell antigen receptors (TCRs) are preferentially expanded, but whether affinity maturation by clonal selection continues through the course of chronic infections remains unresolved. Here we investigated the evolution of the TCR repertoire and its affinity during the course of infection with cytomegalovirus, which elicits large T cell populations in humans and mice.