A virtual memory CD8 T cell-originated subset causes alopecia areata through innate-like cytotoxicity.

Virtual memory T (T) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although T cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a T cell-originated CD44CD49d CD8 T cell subset with features of tissue residency.

KIRCD8 and NKG2ACD8 T cells are distinct innate-like populations in humans.

Subsets of the human CD8 T cell population express inhibitory NK cell receptors, such as killer immunoglobulin-like receptors (KIRs) and NKG2A. In the present study, we examine the phenotypic and functional characteristics of KIRCD8 T cells and NKG2ACD8 T cells. KIRs and NKG2A tend to be expressed by human CD8 T cells in a mutually exclusive manner.

IFITM3 Is Upregulated Characteristically in IL-15-Mediated Bystander-Activated CD8 T Cells during Influenza Infection.

In bystander activation, pre-existing memory CD8 T cells unrelated to the infecting microbes are activated by cytokines without cognate Ags. The detailed mechanisms and unique gene signature of bystander activation remain to be elucidated. In this study, we investigated bystander activation of OT-1 memory cells in a mouse model of influenza infection.

Tumour-infiltrating bystander CD8 T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer.

Background: Tumour-unrelated, virus-specific bystander CD8 T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet.

Methods: We studied the characteristics of bystander CD8 TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy.

Significance of bystander T cell activation in microbial infection.

During microbial infection, pre-existing memory CD8 T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. Studies in mouse models and human patients demonstrate bystander activation of memory CD8 T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8 T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8 T cells.

Abnormality in the NK-cell population is prolonged in severe COVID-19 patients.

Background: Our understanding of adaptive immune responses in patients with coronavirus disease 2019 (COVID-19) is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient.

Objective: We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19.

Methods: We performed RNA sequencing and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved PBMCs.

IL-15 enhances CCR5-mediated migration of memory CD8 T cells by upregulating CCR5 expression in the absence of TCR stimulation.

During microbial infection, bystander CD8 T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8 T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8 T cells and their migration.

Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade.

Background: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.

Methods: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.

Implication of CD69 CD103 tissue-resident-like CD8 T cells as a potential immunotherapeutic target for cholangiocarcinoma.

Background: The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8 T cells (CD8 TILs) from ICC patients.

Methods: From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33).

TOX-expressing terminally exhausted tumor-infiltrating CD8 T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8 tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8 TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer.

PD-1 blockade-unresponsive human tumor-infiltrating CD8 T cells are marked by loss of CD28 expression and rescued by IL-15.

Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8 T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8 T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8 T cells (CD8 TILs) obtained from non-small-cell lung cancer patients.

Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy.

Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction.

4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8 T Cells in Hepatocellular Carcinoma.

Background And Aims: Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8 T cells (CD8 tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8 TILs in hepatocellular carcinoma (HCC).

Approach And Results: Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79).

HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter.