Biomedical subjects

Roza I Nurieva

Publications and source records attributed to Roza I Nurieva.

7 recordsLinked to original sources

PubMed2006

Opposing effects of ICOS on graft-versus-host disease mediated by CD4 and CD8 T cells.

ICOS, a CD28 family member expressed on activated CD4(+) and CD8(+) T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4(+) or CD8(+) T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS(-/-) CD4(+) T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS(-/-) CD4(+) T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-gamma and TNF-alpha. Thus, ICOS(-/-) CD4(+) T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS(-/-) CD8(+) T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8(+) T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS(-/-) CD8(+) T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4(+) and CD8(+) T cells in GVHD.

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PubMed2005

Regulation of immune and autoimmune responses by ICOS-B7h interaction.

Proper T cell activation and function are regulated by the innate immune system, importantly through positive and negative costimulatory molecules of the B7 superfamily. Inducible costimulator (ICOS) is expressed on T cells after T cell activation. A ligand for ICOS, B7h (also known as B7RP-1), is expressed on B cells and induced in nonlymphoid tissues by TNF-alpha. The wide distribution of B7h may play essential roles in different phases and types of immune function. In this review, we summarize the latest data about inducible costimulator and its receptor and their roles in regulation of immune and autoimmune responses.

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PubMed2003

B7h is required for T cell activation, differentiation, and effector function.

T helper (Th) cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a recently identified costimulatory receptor expressed on activated T cells. A ligand for ICOS, B7h, is expressed on B cells and other types of antigen-presenting cells (APC). Although ICOS has been shown to be essential in T cell activation and differentiation, the regulatory roles of B7h at different stages of T cell immune responses have not been examined genetically. In this study, we generated and analyzed B7h-deficient mice. We present evidence that B7h is the only ligand for ICOS, and ICOS, its only corresponding receptor. Th cells, when activated with B7h-deficient APC, exhibited reduced proliferation and IL-2 production. In addition, Th cells produced significantly reduced amounts of IL-4 and -13 after differentiation at the presence of B7h-/- APC. This cytokine defect was associated with a deficiency in c-Maf expression and could be rescued completely by c-Maf overexpression in T cells. Furthermore, we showed that effector T cells, when restimulated in the presence of B7h-deficient APC, exhibited reduced Th2 cytokine production. Therefore, B7h is required for proper Th cell activation, differentiation, and effector cytokine expression.

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PubMed2003

Regulation of immune and autoimmune responses by ICOS.

Proper T cell activation and function are regulated by the innate immune system, importantly through positive and negative costimulatory molecules in the B7 superfamily. Inducible costimulator (ICOS), the receptor for B7h (also known as B7RP-1), is expressed on T cells after T cell activation. Recently, using ICOS-deficient mice, we have examined the roles of ICOS in immune responses. ICOS is required for humoral immunity. In organ-specific autoimmune responses, however, ICOS has contrast roles in different disease models. On the one hand, ICOS-/- mice exhibited extreme sensitivity to experimental autoimmune encephalomyelitis (EAE); on the other, ICOS gene deletion led to complete resistance to collagen-induced arthritis (CIA) in mice. Our work not only illustrates the complexity of immune regulation by costimulatory molecules, but also suggests novel therapeutic strategies for various autoimmune diseases.

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PubMed2003

Transcriptional regulation of th2 differentiation by inducible costimulator.

Helper T (Th) cell differentiation is accompanied by complex transcriptional changes. Although costimulatory receptors are important in Th differentiation, the underlying mechanisms are poorly understood. Here we examine the transcriptional mechanisms by which ICOS regulates Th2 differentiation and selective IL-4 expression by effector T cells. We found impaired expression of c-Maf transcription factor functionally associated with the IL-4 defect in ICOS(-/-) cells. c-Maf expression in effector cells was regulated by IL-4 levels during Th differentiation. ICOS costimulation potentiated the T cell receptor (TcR)-mediated initial IL-4 production, possibly through the enhancement of NFATc1 expression. These data indicate that ICOS, by enhancing TcR signals at an early stage of T cell activation, regulates IL-4 transcription and T cell function in effector cells.

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PubMed2003

Inducible costimulator is essential for collagen-induced arthritis.

CD4(+) helper Th cells play a major role in the pathogenesis of rheumatoid arthritis. Th cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a novel costimulatory receptor expressed on activated T cells. We, as well as others, recently demonstrated its importance in Th2 cytokine expression and Ab class switching by B cells. In this study, we examined the role of ICOS in rheumatoid arthritis using a collagen-induced arthritis model. We found that ICOS knockout mice on the DBA/1 background were completely resistant to collagen-induced arthritis and exhibited absence of joint tissue inflammation. These mice, when immunized with collagen, exhibited reduced anti-collagen IgM Ab's in the initial stage and IgG2a Ab's at the effector phase of collagen-induced arthritis. Furthermore, ICOS regulates the in vitro and in vivo expression of IL-17, a proinflammatory cytokine implicated in rheumatoid arthritis. These data indicate that ICOS is essential for collagen-induced arthritis and may suggest novel means for treating patients with rheumatoid arthritis.

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PubMed2003

Immune regulation by novel costimulatory molecules.

CD4 helper T (Th)-cells and the cytokines that they produce play essential regulatory roles in immune and autoimmune responses. Th activation and differentiation is regulated by costimulatory receptors. CD28 and CTLA-4 are important in maintaining the threshold of T-cell activation. ICOS and PD-1 are novel costimulatory receptors expressed on activated T-cells. B7-H3 recognizes a putative costimulatory receptor on activated T-cells. Here we summarize the latest developments in the novel costimulatory molecules and their roles in regulating Th activation, differentiation, and function.

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