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G P Brooke

Publications and source records attributed to G P Brooke.

5 recordsLinked to original sources
PubMed2002

Co-stimulation and modulation of the ensuing immune response.

As a consequence of the central role of dendritic cells (DC) in stimulating primary immune responses any bias in the response introduced by the DC has the potential for having a long-term effect on immunity. Examination and analysis of ruminant afferent lymph dendritic cells derived by cannulation allows studies on the properties of ex vivo DC that is not possible in humans and rodents and information can be derived from ruminants that has implications of generic relevance. Previous studies have identified two major populations of DC in afferent lymph draining the skin of cattle that differ in their capacity to stimulate CD4 and CD8 T cells. Differences in expression of cytokine transcripts have now been shown for the two types of DC. The CD11a(+)/SIRPalpha(-) population synthesised more IL-12, whilst the CD11a(-)/SIRPalpha(+) population produced more IL-10. This is likely to affect the bias of the immune response following presentation of antigen to T cells by one DC sub-population or the other. An inability to synthesise IL-1alpha was the reason for the failure of the CD11a(+)/SIRPalpha(-) DC to stimulate CD8 T cells. This property would potentially affect the induction of CD8 responses. Expression of the co-stimulatory molecules CD80, CD86 and CD40 appeared similar for both DC populations and not to relate to differences in function. A further examination of the SIRPalpha molecule on DC indicated that on cross-linking it was tyrosine phosphorylated and that it recruited the SHP-2 protein phosphatase. Associated with this was a blocking of TNFalpha secretion on exposure to LPS. The interaction of SIRPalpha with its ligand CD47 on T cells appeared to be an early event in the stimulation of T cells as binding of the ligand was reduced on activated T cells. CD26 was identified as another molecule expressed by the SIRPalpha(-) DC sub-population. This is reported to have an enzymatic activity on certain chemokines that could result in the promotion of a Th1 bias.A model is proposed that takes these observations into account in which SIRPalpha(-) DC would be expected to promote a Th1 biased response and the SIRPalpha(+) DC a more balanced one.

Animals↗
PubMed1999

Dendritic cells in cattle: phenotype and function.

Dendritic cells are professional antigen presenting cells derived from the bone marrow and distributed throughout body tissues where they are located in sites that are suitable for antigen uptake. They are central to the induction of immune responses in naive animals and thus have become targets in strategies that are aimed at modulating resistance to infection. Studies in cattle have shown that the dendritic cells are phenotypically heterogeneous and that the different phenotypes have different biological properties. The molecular basis for this variation has begun to be investigated and has led to the identification of a member of the SIRPalpha family of signal regulatory proteins (MyD1) on a subset of dendritic cells in afferent lymph. Uptake of antigen by cattle dendritic cells is by a number of mechanisms that can involve endocytosis via clathrin coated pits or via caveolae as well as macropinocytosis.

Animals↗
PubMed1998

Cloning of two members of the SIRP alpha family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells.

Recent experimental studies have greatly clarified the function of cell surface molecules in the induction and modulation of T cell responses by antigen-presenting cells (APC). However, the differences in ability to stimulate T cells evident for different types and subpopulations of the same APC, such as dendritic cell subsets, is less well understood. This report details an investigation of an antigen expressed on monocytes that is also expressed on a subset of cattle afferent lymph veiled cells (ALVC). A cDNA library derived from cattle monocytes was screened with monoclonal antibodies (mAb) for expression in COS-7 cells. Using separate mAb for screening, two cDNA were cloned, the sequences of which showed a single long open reading frame encoding a predicted type I glycoprotein of 506 amino acids that contained three immunoglobulin superfamily domains and a long 112-amino acid cytoplasmic tail. We have termed this antigen MyD-1, reflecting its myeloid and dendritic cell distribution. Analysis of the EMBL database revealed that the molecule is a member of the recently described family of signal regulatory proteins (SIRP). The outeremost Ig domain was of the adhesion/receptor I-type, suggesting that MyD-1 might bind to a ligand on another cell. Evidence for this was subsequently obtained by demonstrating that COS-7 cells transfected with MyD-1 cDNA bound CD4 T cells and this binding was blocked by specific mAb. The potential importance of this interaction was supported by the finding that the proliferation of resting memory CD4 T cells to ovalbumin-pulsed monocytes was significantly reduced in the presence of mAb to MyD-1. A role for the molecule in the modulation of the monocyte/dendritic APC response is also predicted from the existence of multiple potential tyrosine phosphorylation sites in the cytoplasmic domain, including the presence of an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the observation that the SIRP alpha family members have been shown to bind to SHP-1 and SHP-2. Together these data indicate a possible functional importance for MyD-1 in the regulation of monocyte and dendritic cell function.

Amino Acid Sequence↗