Inhibiting the NADase CD38 improves cytomegalovirus-specific CD8+ T cell functionality and metabolism.

Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in people who are immunocompromised, such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in people who are immunosuppressed have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in patients who are immunocompromised and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with noncontrolled CMV infection.

Intestinal tissue-resident memory T cells maintain distinct identity from circulating memory T cells after in vitro restimulation.

Resident memory T (T) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that T expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggests an opportunity for in vitro T expansion to apply in an immunotherapy setting.

E-Cadherin Expression Distinguishes Mouse from Human Hematopoiesis in the Basophil and Erythroid Lineages.

E-cadherin is a key regulator of epithelial cell-cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive.

CRISPR Activation Screening Identifies VGLL3-TEAD1-RUNX1/3 as a Transcriptional Complex for PD-L1 Expression.

The PD-L1/2-PD-1 immune checkpoint is essential for the proper induction of peripheral tolerance and limits autoimmunity, whereas tumor cells exploit their expression to promote immune evasion. Many different cell types express PD-L1/2, either constitutively or upon stimulation, but the factors driving this expression are often poorly defined. In this study, using genome-wide CRISPR activation screening, we identified three factors that upregulate PD-L1 expression: GATA2, MBD6, and transcription cofactor vestigial-like protein 3 (VGLL3).

A third vaccination with a single T cell epitope confers protection in a murine model of SARS-CoV-2 infection.

Understanding the mechanisms and impact of booster vaccinations are essential in the design and delivery of vaccination programs. Here we show that a three dose regimen of a synthetic peptide vaccine elicits an accruing CD8 T cell response against one SARS-CoV-2 Spike epitope. We see protection against lethal SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model in the absence of neutralizing antibodies, but two dose approaches are insufficient to confer protection.

Hobit and Blimp-1 regulate T abundance after LCMV infection by suppressing tissue exit pathways of T precursors.

Tissue-resident memory T cells (Trm) are retained in peripheral tissues after infection for enhanced protection against secondary encounter with the same pathogen. We have previously shown that the transcription factor Hobit and its homolog Blimp-1 drive Trm development after viral infection, but how and when these transcription factors mediate Trm formation remains poorly understood. In particular, the major impact of Blimp-1 in regulating several aspects of effector T-cell differentiation impairs study of its specific role in Trm development.

Hobit identifies tissue-resident memory T cell precursors that are regulated by Eomes.

Tissue-resident memory CD8 T cells (T) constitute a noncirculating memory T cell subset that provides early protection against reinfection. However, how T arise from antigen-triggered T cells has remained unclear. Exploiting the T-restricted expression of Hobit, we used T reporter/deleter mice to study T differentiation.

Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells.

Tissue-resident memory T (T) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. T cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of T cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues.

Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer.

Background: Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8 T cells elicited upon immunization with adenoviral vectors.

Circulating memory CD8 T cells are limited in forming CD103 tissue-resident memory T cells at mucosal sites after reinfection.

Tissue-resident memory CD8 T cells (T ) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (T ) and effector memory CD8 T cells (T ) also contribute to tissue recall responses, but their potential to form mucosal T remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of T and T at mucosal sites.

Tissue-resident memory CD8 T cells shape local and systemic secondary T cell responses.

Tissue-resident memory CD8 T cells (T cells) are crucial in protecting against reinvading pathogens, but the impact of reinfection on their tissue confinement and contribution to recall responses is unclear. We developed a unique lineage tracer mouse model exploiting the T-defining transcription factor homolog of Blimp-1 in T cells (Hobit) to fate map the T progeny in secondary responses. After reinfection, a sizeable fraction of secondary memory T cells in the circulation developed downstream of T cells.

Murine iNKT cells are depleted by liver damage via activation of P2RX7.

Invariant natural killer T cells (iNKT) constitute up to 50% of liver lymphocytes and contribute to immunosurveillance as well as pathogenesis of the liver. Systemic activation of iNKT cells induces acute immune-mediated liver injury. However, how tissue damage events regulate iNKT cell function and homeostasis remains unclear.

Blimp-1 Rather Than Hobit Drives the Formation of Tissue-Resident Memory CD8 T Cells in the Lungs.

Tissue-resident memory CD8 T (T) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8 T cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8 T cells. In contrast to CD8 T cells at these sites, CD8 T cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence.

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Tissue-resident memory T cells (T) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes T to tissue damage. This history of danger-signal exposure is an important aspect of T-mediated immunity that has been overlooked so far.

Armed and Ready: Transcriptional Regulation of Tissue-Resident Memory CD8 T Cells.

A fundamental benefit of immunological memory is the ability to respond in an enhanced manner upon secondary encounter with the same pathogen. Tissue-resident memory CD8 T (T) cells contribute to improved protection against reinfection through the generation of immediate effector responses at the site of pathogen entry. Key to the potential of T cells to develop rapid recall responses is their location within the epithelia of the skin, lungs, and intestines at prime entry sites of pathogens.

Blimp-1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells.

CD8 T cells acquire cytotoxic molecules including granzyme B during effector differentiation. Both tissue-resident memory CD8 T cells (Trm) and circulating CD45RA effector-type T cells (Temra) cells have the ability to retain granzyme B protein expression into the memory phase, but it is unclear how this persistence of cytolytic activity is regulated during steady state. Previously, we have described that the transcriptional regulators Hobit and Blimp-1 have overlapping target genes that include granzyme B, but their impact on the regulation of cytotoxicity in Trm and Temra cells during homeostasis has remained unclear.

Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes.

Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice.