Absence of B7-dependent responses in CD28-deficient mice

Green, Jonathan M.; Noël, Patricia; Sperling, Anne I.; Walunas, Theresa L.; Gray, Gary S.; Bluestone, Jeffrey A.; Thompson, Craig B.

doi:10.1016/1074-7613(94)90092-2

Cited by 355 publications

(223 citation statements)

References 24 publications

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“…It has been suggested that the strength of TCR-mediated signals may dictate the level of second signal costimulation that is required in order to achieve T cell activation [61]. This idea is supported by the observation that CD28 -/-T cells will proliferate in response to higher doses of anti-CD3 in vitro [62] and by studies that have shown that prolonged TCR stimulation in CD28 -/-mice prevents T cell anergy and allows for the generation of functional CTL responses in these mice [63]. Thus, antigen dose and the degree of TCR ligation may be an issue in regard to the requirement for CD40/CD154 costimulation.…”

Section: What Determines Cd40/cd154-dependence?supporting

confidence: 60%

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

Mackey

Barth

Noelle

1998

Journal of Leukocyte Biology

197

137

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This review focuses on the emerging body of literature suggesting a critical role for CD40/CD154 interactions in antigen-presenting cell (APC) activation, CD4 ؉ and CD8 ؉ T cell priming, and effector T cell maturation. In this context effective antigen presentation involves not only T cell expansion and long-term survival but also the ability of the APC to guide the T cell response toward the Th1 (interferon-␥ producing) or the Th2 (interleukin-4 producing) phenotype. We suggest a model to explain why CD40/CD154 interactions are critical for some helper and cytotoxic T cell responses, whereas others occur independently of this receptor/ligand pair. In addition, we will discuss the potential role for CD40/CD154 interactions in effector T cell maturation and cytokine production.

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Section: What Determines Cd40/cd154-dependence?supporting

confidence: 60%

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

Mackey

Barth

Noelle

1998

Journal of Leukocyte Biology

197

137

View full text Add to dashboard Cite

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“…This notion is supported by the fact that CD80 and CD86 genes appear to be results of a gene duplication (17), yet they currently only share ϳ25% of their amino acids (3,18,19). In addition, the severe phenotype of CD28-and CTLA-4-deficient mice (4,5,8,(12)(13)(14) and the structurally conserved ligand binding sites of suggest that natural evolution has strongly favored the binding of B7 molecules to both of their respective ligands. Directed molecular evolution by DNA shuffling followed by screening has previously been successful in evolving, for example, subtilisin, interferon ␣, viruses, and bacteria (25-31).…”

mentioning

confidence: 59%

Chimeric Co-stimulatory Molecules That Selectively Act through CD28 or CTLA-4 on Human T Cells

Lazetic

Leong

Chang

et al. 2002

Journal of Biological Chemistry

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CD28 and CTLA-4 (CD152) play a pivotal role in the regulation of T cell activation. Upon ligation by CD80 (B7-1) or CD86 (B7-2), CD28 induces T cell proliferation, cytokine production, and effector functions, whereas CTLA-4 signaling inhibits expansion of activated T cells and induces tolerance. Therefore, we hypothesized that co-stimulatory molecules that preferentially bind CD28 or CTLA-4 would have dramatically altered biological properties. We describe directed molecular evolution of CD80 genes derived from human, orangutan, rhesus monkey, baboon, cat, cow, and rabbit by DNA shuffling and screening. In contrast to wild-type CD80, the evolved co-stimulatory molecules, termed CD28-binding protein (CD28BP) and CTLA-4-binding protein (CTLA-4BP), selectively bind to CD28 or CTLA-4, respectively. Furthermore, CD28BP has improved capacity to induce human T cell proliferation and interferon-␥ production compared with wild-type CD80. In contrast, CTLA-4BP inhibited human mixed leukocyte reaction (MLR) and enhanced interleukin 10 production in MLR, supporting a role for CTLA-4BP in inducing T cell anergy and tolerance. In addition, co-stimulation of purified human T cells was significantly suppressed when CTLA-4BP was cotransfected with either CD80 or CD28BP. The amino acid sequences of CD28BP and CTLA-4BP were 61 and 96% identical with that of human CD80 and provide insight into the residues that are critical in the ligand binding. These molecules provide a new approach to characterization of CD28 and CTLA-4 signals and to manipulation of the T cell response.T cell response is dependent on complex integration of antigen-specific and nonspecific extracellular and intracellular signals. The specificity of the response is determined by recognition of an antigenic peptide in the context of major histocompatibility complex on the plasma membrane of antigen-presenting cells, such as monocytes, dendritic cells, Langerhans cells, or primed B cells. However, a second signal, mediated by co-stimulatory molecules expressed on antigenpresenting cells, is required for induction of a complete T cell response (1-3). The most extensively studied co-stimulatory molecules are CD80 (B7-1) and CD86 (B7-2), which bind the CD28 and CTLA-4 (CD152) ligands expressed on CD4 ϩ and CD8 ϩ T cells. Additional co-stimulatory molecule-ligand pairs such as ICOS-B7-H and PD1-PDL have recently been identified, further illustrating the complexity of the signals that regulate the function of T cells (1-3). Co-stimulatory signal in addition to the T cell receptor signal is a prerequisite for induction of optimal T activation, proliferation, cytokine production, and effector functions.The functional characterization of CD80, CD86, CD28, and CTLA-4 has also illustrated the delicate balance between positive and negative signals mediated through CD28 and CTLA-4, respectively. Upon ligation by CD80 or CD86, CD28 synergizes with T cell receptor signaling to induce activation of both CD4 ϩ and CD8 ϩ T cells (4 -7), whereas CTLA-4 ligation inhibits expansion of...

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“…CD28-deficient mice show reduced basal levels of IgG1 and IgG2b, increased IgG2a, and inefficient help to B cells (50,51). In addition, IL-4 production and, to a lesser extent, IFN-␥ production have been shown to be regulated by CD28-mediated signals (52,53).…”

Section: Discussionmentioning

confidence: 99%

Akt Is a Neutral Amplifier for Th Cell Differentiation

Arimura

Shiroki

Kuwahara

et al. 2004

Journal of Biological Chemistry

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Both CD28 and its relative, inducible costimulator (ICOS), have a binding motif for phosphatidylinositol 3-kinase (PI3K) in their cytoplasmic tail, and the binding of PI3K leads to activation of a serine/threonine kinase, Akt. The role of Akt in cytokine production and helper T (Th) cell differentiation remains obscure. In this study, we found that enforced expression of the constitutively active form (E40K) of Akt rendered CD4 ؉ T cells activated. Wild-type of Akt and E40K promoted Th1 cell differentiation in C57BL/6-derived and Th1-polarized BALB/c-derived CD4 ؉ T cells, while both promoted Th2 cell differentiation in BALB/c-derived and Th2-polarized C57BL/6 CD4 ؉ T cells. E40K also facilitated Th1 differentiation in CD4 ؉ T cells from IL-4-deficient mice with the BALB/c background. E40K up-regulated expression of NF-AT and c-Myb, which may be related to the augmentation of cytokine production by E40K. These findings indicate that the mechanism by which Akt augments cytokine production via CD28 and ICOS is Th cell type-specific and reflects the intracellular status affected by the cytokine milieu. We conclude that Akt is a neutral amplifier of T cell activation and Th differentiation.

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Absence of B7-dependent responses in CD28-deficient mice

Cited by 355 publications

References 24 publications

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

Chimeric Co-stimulatory Molecules That Selectively Act through CD28 or CTLA-4 on Human T Cells

Akt Is a Neutral Amplifier for Th Cell Differentiation

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