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Christopher E Rudd

Publications and source records attributed to Christopher E Rudd.

27 records · Page 2Linked to original sources
PubMed2003

Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation.

The two-signal theory of T-cell activation dictates that optimal T-cell responses are determined by a least two signals, the primary signal provided by the antigen-receptor complex (TCR/CD3) and the second signal provided by a costimulatory receptor. Recent studies have underlined the importance of in trans costimulation via CD28 in the regulation of transplant rejection. Previous studies have emphasized the ability of CD28 to operate in cis in the amplification of signaling through the T-cell receptor (TCR). Our recent work has demonstrated that CD28 can activate the lipid kinase phosphatidylinositol 3-kinase (PI-3K) and can cooperate with adapters Vav and SLP-76 to influence the induction of interleukin (IL)-2 and IL-4 transcription in the absence of TCR ligation. CD28-PI-3K binding and CD28-VAV/SLP-76 cooperativity provide a pathway to account for in trans costimulation in T-cell immunity.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.

Many studies have shown the central importance of the co-receptors CD28, inducible costimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) in the regulation of many aspects of T-cell function. CD28 and ICOS have both overlapping and distinct functions in the positive regulation of T-cell responses, whereas CTLA4 negatively regulates the response. The signalling pathways that underlie the function of each of the co-receptors indicate their shared and unique properties and provide compelling hints of functions that are as yet uncovered. Here, we outline the shared and distinct signalling events that are associated with each of the co-receptors and provide unifying concepts that are related to signalling functions of these co-receptors.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2003

Hematopoietic adaptors in T-cell signaling: potential applications to transplantation.

Recent advances have been made in understanding the basis of T-cell signaling with the identification of hematopoeitic-specific adaptor proteins, or molecular scaffolds that facilitate protein complex formation and the integration of signals from the surface of T cells. Their potential relevance as targets in the modulation of transplantation relates to their immune-cell-specific expression and their ability to integrate signals needed for T-cell/APC conjugate formation, cytokine production and the clonal expansion of T cells. While LAT, GADS and SLP-76 are needed for TcR-induced cytokine production, the adaptors ADAP, VAV and SKAP-55 play specialized roles in the regulation of integrin adhesion and conjugation. Given the importance of these functions to the reactivity of T cells to allodeterminants of tissue grafts (GvH), and in the recognition and destruction of leukemic cells (GvL), these adaptors represent a new generation of potential targets in the modulation of transplantation.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Short cytoplasmic SDYMNM segment of CD28 is sufficient to convert CTLA-4 to a positive signaling receptor.

CD28 and cytotoxic T-lymphocyte antigen (CTLA)-4 are key coreceptors on the surface of T cells that have opposing effects on T cell activation. Although CD28 enhances proliferation, CTLA-4 markedly inhibits the activation process. These opposing roles are particularly surprising given the structural similarity of the cytoplasmic residues of the two receptors. These include the related CD28(SDYMNM) and CTLA-4(GVYVKM) motifs. In this study, we have directly addressed whether these related motifs may play different roles in the activation process by swapping the CTLA-4(GVYVKM) motif with the CD28(SDYMNM) motif. Remarkably, stable transfectants of the T cell hybridoma DC27.10 showed that substitution of CTLA-4(GVYVKM) was sufficient to convert CTLA-4 from a negative signaling coreceptor to a positive CD28-like coreceptor. CD28(SDYMNM) is therefore sufficient to convey positive signals within CTLA-4. These results demonstrate that CD28(SDYMNM) and CTLA-4(GVYVKM) motifs contain sufficient information to distinguish positive versus negative coreceptor signaling in T cells.

Abatacept↗
PubMed2002

Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from receptor/ligand-deficient mice.

Although CTLA-4 (CD152) has potent inhibitory effects on T cell function, the signaling events affected by this coreceptor remain to be fully defined. Mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) act as crucial regulators of multiple aspects of cell function. Ab ligation studies have reported an inhibitory effect of CTLA-4 on TCR-induced ERK and JNK activation. In this study, we have re-examined the specificity of CTLA-4 inhibition of MAPKs by using natural ligand with ex vivo-purified CD4(+) T cells deficient in CD80 and CD86 (double knockout), or CTLA-4, CD80, and CD86 (triple knockout). Under these conditions, CTLA-4 ligation was found to up-regulate and sustain JNK activation, while inhibiting ERK activity. At the same time, JNK activation could not account for CTLA-4 induction of TGF-beta production. Our findings demonstrate that CTLA-4 cosignaling is more complex than previously appreciated, with an ability to differentially regulate members of the MAPK family in T cells.

Abatacept↗
PubMed2002

CTLA-4 negative signaling via lipid rafts: A new perspective.

Proper function of the immune system requires that activation of T cells is precisely regulated. Responses to the T cell receptor are modulated by signals from other receptors. CTLA-4 (cytotoxic T lymphocyte antigen-4, also called CD152), for example, inhibits cytokine production and proliferation of T cells. Activation of T cells is associated with the accumulation of signaling proteins in lipd rafts--microdomains of the plasma membrane enriched in cholesterol and glycosphingolipds. Rudd et al. discuss evidence that CTLA-4 might inhibit cytokine production and T cell proliferation by limiting the assembly of lipid rafts, which are critical to the formation of a functional immunological synapse between antigen-presenting cells and T cells.

Abatacept↗
PubMed2002

Protein tyrosine phosphorylation in T cell signaling.

This review discusses in considerable detail the tyrosine phosphorylation events that couple the T cell antigen receptor to downstream signaling pathways. First, the protein kinases that catalyze these tyrosine phosphorylation are introduced, then the phosphatases that mediate removal of phosphate from tyrosine residues. Next, we discuss the molecular clock work by which these enzymes initiated T cell activation. Finally, we briefly review the key substrates for tyrosine phosphorylation and their role in coupling the kinases and phosphatases to gene transcription and other aspects of the T lymphocyte response to antigen.

Animals↗
PubMed2001

Phosphatidylinositol 3-kinase p85 adaptor function in T-cells. Co-stimulation and regulation of cytokine transcription independent of associated p110.

Phosphatidylinositol 3-kinase (PI3K) is a key regulator of a variety of cellular functions from cytoskeletal organization, vesicular trafficking, and cell proliferation to apoptosis. The enzyme complex is comprised of an 85-kDa adaptor (p85) coupled to a 110-kDa catalytic subunit (p110). While the function of PI3K has been largely attributed to the generation of D-3 lipids, an unanswered question has been whether p85 with a number of motifs (SH2, SH3, BcR homology (BH) region) can generate independent intracellular signals. In this study, we demonstrate that p85 lacking p110 (Deltap85) can activate NFAT transcription in T-cell hybridomas and normal splenocytes. This up-regulatory effect was unaffected by inhibition of PI 3-kinase, and cooperated specifically with Rac1, but not related family members. Stimulation correlated with Rac1 binding and was lost with the deletion of the BH domain. Lastly, the CD28-Deltap85 chimera also cooperated with TcR/CD3 to provide co-signals that enhanced IL-2 transcription. Our findings identify for the first time p85 as an adaptor that operates independently of the classic PI 3-kinase catalytic pathway and further shows that this pathway can provide co-signals in the regulation of T-cell function.

Androstadienes↗