IL-4/IL-4 Ab complex enhances the accumulation of both antigen-specific and bystander CD8 T cells in mouse lungs infected with influenza A virus.

Background: Unlike conventional T cells, innate and virtual-memory CD8 T cells in naïve mice acquire their memory phenotypes and functions in the absence of antigenic encounters in a cytokine-dependent manner. The relevant cytokines include interleukin-4 (IL-4), type I interferon, and interleukin-15 (IL-15). Moreover, exogenous IL-4 can also induce de novo generation and/or expansion of the virtual-memory CD8 T cell population.

Prevention of severe lung immunopathology associated with influenza infection through adeno-associated virus vector administration.

Background: Influenza A viruses (IAVs) have long posed a threat to humans, occasionally causing significant morbidity and mortality. The initial immune response is triggered by infected epithelial cells, alveolar macrophages and dendritic cells. However, an exaggerated innate immune response can result in severe lung injury and even host mortality.

CD1b glycoprotein, a crucial marker of thymocyte development during T cell maturation in cynomolgus monkeys.

Phenotypic markers that denote different developmental stages of thymocytes are important for understanding T cell development in the thymus. Here, we show that CD1b is a critical discriminator of thymocyte maturation stage in cynomolgus monkeys. CD1b was expressed by immature thymocytes prior to β-selection, and its expression decreased as cells became fully mature in the thymus.

Heterogeneity of circulating CD4CD8 double-positive T cells characterized by scRNA-seq analysis and trajectory inference.

The frequency of CD4CD8 double-positive (DP) T cells is highly associated with a variety of diseases. Recently, we used high-throughput single-cell RNA sequencing to show that circulating DP T cells in cynomolgus monkeys comprise nine heterogeneous populations. To better understand the characteristics of DP T cells, we analyzed 7601 cells from a rhesus monkey and detected 14,459 genes.

Cellular heterogeneity of circulating CD4CD8 double-positive T cells characterized by single-cell RNA sequencing.

Circulating CD4CD8 double-positive (DP) T cells are associated with a variety of disease states. However, unlike conventional T cells, the composition of this population is poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to analyze the composition and characteristics of the DP T cell population circulating in the peripheral blood of cynomolgus monkeys.

UVB-induced depletion of donor-derived dendritic cells prevents allograft rejection of immune-privileged hair follicles in humanized mice.

Dendritic cells (DCs) are key targets for immunity and tolerance induction; they present donor antigens to recipient T cells by donor- and recipient-derived pathways. Donor-derived DCs, which are critical during the acute posttransplant period, can be depleted in graft tissue by forced migration via ultraviolet B light (UVB) irradiation. Here, we investigated the tolerogenic potential of donor-derived DC depletion through in vivo and ex vivo UVB preirradiation (UV) combined with the injection of anti-CD154 antibody (Ab) into recipients in an MHC-mismatched hair follicle (HF) allograft model in humanized mice.

Attenuation of Experimental Autoimmune Encephalomyelitis in a Common Marmoset Model by Dendritic Cell-Modulating Anti-ICAM-1 Antibody, MD-3.

MD-3 is a novel anti-human ICAM-1 monoclonal antibody that induces T cell tolerance in humanized mice via modulation of dendritic cell differentiation and efficiently suppresses the development of collagen-induced arthritis. This effect has also been observed in xenograft rejection in nonhuman primates, where grafts survived for more than 2.5 years following MD-3 administration.

CD4CD8 Double-Positive T Cells Are Associated with Graft Rejection in a Nonhuman Primate Model of Islet Transplantation.

Peripheral CD4/CD8 double-positive (DP) T cells are associated with autoimmune disorders, cancer, and viral infection. However, the relationship between organ transplantation and DP T cells is unclear. Here, we examined the functional characteristics of peripheral DP T cells and analyzed their significance with respect to islet graft rejection in a nonhuman primate model of islet transplantation.

Epitope-based ligation of ICAM-1: Therapeutic target for protection against the development of rheumatoid arthritis.

Identification of a particular epitope on the domain 2 of human ICAM-1 led us to focus on its role in the treatment of rheumatoid arthritis (RA). Key observations from our previous xenotransplantation research included the generation of tolerogenic DCs, antigen-specific T-cell tolerance, and reduced production of inflammatory cytokines. The critically important point is the fact that it works initially on DC maturation.

RD-05, a novel anti-CD154 antibody, efficiently inhibits generation of anti-drug antibody without the risk of thrombus formation in non-human primates.

Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies.

The effect of epitope-based ligation of ICAM-1 on survival and retransplantation of pig islets in nonhuman primates.

Background: Pig islet xenotransplantation is a promising alternative to allogeneic transplantation. However, the wide immunologic barrier between pigs and primates limits the long-term survival of the graft. MD-3, a novel monoclonal antibody (mAb) that recognizes a particular epitope of human ICAM-1, can render T cells tolerant to a xenograft by arresting dendritic cell maturation.

Effect of IL-4 on the Development and Function of Memory-like CD8 T Cells in the Peripheral Lymphoid Tissues.

Unlike conventional T cells, innate CD8 T cells develop a memory-like phenotype in the thymus and immediately respond upon antigen stimulation, similar to memory T cells. The development of innate CD8 T cells in the thymus is known to require IL-4, which upregulates Eomesodermin (Eomes). These features are similar to that of virtual memory CD8 T cells and IL-4-induced memory-like CD8 T cells generated in the peripheral tissues.

PLZF(+) Innate T Cells Support the TGF-β-Dependent Generation of Activated/Memory-Like Regulatory T Cells.

PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether PLZF(+) innate T cells also affect the development and function of Foxp3(+) regulatory CD4 T cells.