Biomedical subjects

Hidehiro Kishimoto

Publications and source records attributed to Hidehiro Kishimoto.

5 recordsLinked to original sources

PubMed2006

Regulation of naive T cell function by the NF-kappaB2 pathway.

T cell activation involves the orchestration of several signaling pathways, including that of the 'classical' transcription factor NF-kappaB components NF-kappaB1-RelA. The function of the 'nonclassical' NF-kappaB2-RelB pathway is less clear, although T cells lacking components of this pathway have activation defects. Here we show that mice deficient in NF-kappaB-inducing kinase have a complex phenotype consisting of immunosuppression mediated by CD25(-)Foxp3(-) memory CD4(+) cells and, in the absence of those cells, hyper-responsive naive CD4(+) T cells, which caused autoimmune lesions after adoptive transfer into hosts deficient in recombination-activating genes. Biochemical studies indicated involvement of a cell-intrinsic mechanism in which NF-kappaB2 (p100) limits nuclear translocation of NF-kappaB1-RelA and thereby functions as a regulatory 'brake' for the activation of naive T cells.

Active Transport, Cell Nucleus↗

PubMed2006

CD28-dependent differentiation into the effector/memory phenotype is essential for induction of arthritis in interleukin-1 receptor antagonist-deficient mice.

OBJECTIVE: Interleukin-1 receptor antagonist (IL-1Ra)-deficient mice on a BALB/c background spontaneously develop a chronic inflammatory polyarthropathy closely resembling that of rheumatoid arthritis in humans. To elucidate the role of CD28 costimulatory signals in the development of this disease, we studied IL-1Ra/CD28-double-deficient mice. METHODS: We crossed IL-1Ra-deficient mice with CD28-deficient mice and observed the incidence and severity of arthritis. To investigate functions of IL-1Ra/CD28-double-deficient T cells, cells were stimulated with CD3 monoclonal antibody or allogeneic antigen-presenting cells (APCs) and their proliferative responses and levels of cytokine production were measured. RESULTS: Disease severity was lower in IL-1Ra/CD28-double-deficient mice than in mice that were deficient only in IL-1Ra, although incidence of arthritis was not affected by the presence or absence of CD28. When pathogenic IL-1Ra-KO T cells were transferred into nude mice, severe arthritis developed. Even though T cells from double-deficient mice showed the same diminished proliferative capacity as was seen in T cells from CD28-single-deficient animals, nude mice into which double-deficient T cells were transferred never developed arthritis. CONCLUSION: These findings indicate that IL-1Ra/CD28-double-deficient T cells can be activated by IL-1Ra-deficient activated APCs, resulting in induction of arthritis; however, these T cells did not induce the disease under normal conditions, because they did not differentiate into effector/memory phenotype.

Animals↗

PubMed2005

Signaling T-cell survival and death by IL-2 and IL-15.

Interleukin 2 (IL-2) and interleukin 15 (IL-15) bind to common T-cell surface receptors comprised of unique alpha (IL-2R alpha or IL-15R alpha) and shared beta/gamma chain subunits. Ligation of this receptor by IL-2 can lead to apoptosis whereas IL-15 ligation favors cell survival. Our study examined intra-cellular signaling events associated with IL-2- and IL-15-induced apoptosis and survival in human T cells. We found IL-2 and IL-15 could both induce apoptosis and survival; the outcome depended on cytokine concentration. No qualitative differences in Jak/Stat, Ras/MAPK or PI3K/AKT signaling were seen over a wide range of IL-2 and IL-15 concentrations. These findings suggest that, like T-cell receptor signaling, IL-2R beta/gamma chain signaling is regulated, or "tuned," by the concentration of cytokine.

Apoptosis↗

PubMed2002

Aging leads to disturbed homeostasis of memory phenotype CD8(+) cells.

Examining the rate of in vivo T cell turnover (proliferation) in aged mice revealed a marked reduction in turnover at the level of memory-phenotype CD44(hi) CD8(+) cells relative to young mice. Based on adoptive transfer experiments, the reduced turnover of aged CD44(hi) CD8(+) cells reflected an inhibitory influence of the aged host environment. Aged CD44(hi) CD8(+) cells also showed poor in vivo responses to IL-15 and IL-15-inducing agents, but responded well to IL-15 in vitro. Two mechanisms could account for the reduced turnover of aged CD44(hi) CD8(+) cells in vivo. First, aging was associated with a prominent and selective increase in Bcl-2 expression in CD44(hi) CD8(+) cells. Hence, the reduced turnover of aged CD44(hi) CD8(+) cells may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of aged CD44(hi) CD8(+) cells to IL-15 correlated with increased serum levels of type I interferons (IFN-I) and was largely reversed by injection of anti-IFN-I antibody. Hence the selective reduction in the turnover of aged CD44(hi) CD8(+) cells in vivo may reflect the combined inhibitory effects of enhanced Bcl-2 expression and high IFN-I levels.

Adoptive Transfer↗

PubMed2002

The thymus and negative selection.

Maintenance of tolerance to self antigens is presumed to reflect a combination of central and peripheral tolerance. For T cells, central tolerance occurs during early T cell development in the thymus and causes cells with strong reactivity to self antigens to be destroyed in situ (negative selection). Here, we summarize evidence that negative selection can occur in the thymic medulla and affects a population of semimature HSA+ T cells. The influence of costimulatory molecules, Fas and cytokines on negative selection is discussed.

Animals↗