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T cell receptor structure and function

The T cell receptor (TCR) is a multi-chain receptor composed of the antigen-recognizing αβ heterodimer and the tightly associated signal-transducing CD3γε, CD3δε and CD3ζζ dimers. Like many other cell surface receptors, the TCR is down-regulated following ligand triggering. At least two distinct pathways exist for TCR down-regulation. One pathway is dependent on protein tyrosine kinase activity and leads to TCR ubiquitination and degradation. The other pathway is dependent on protein kinase C-mediated activation of the di-leucine-based (diL) motif found in the CD3γ chain of the TCR and leads to TCR recycling. The CD3γ diL motif plays a unique role in TCR trafficking, and we have characterized this motif in details at the molecular and cellular level. To study the physiological roles of CD3γ diL motif-mediated TCR down-regulation, we have generated CD3γLLAA knock-in mice homozygous for a double leucine to alanine mutation in the CD3g diL motif. The T Cell Biology group's ongoing studies have demonstrated that dynamic regulation of TCR expression levels by the CD3γ diL motif plays important roles in modulating T cell responses both during T cell development and in mature T cells.

T cell development

Development of T cells progenitors into mature T cells takes place in the thymus. This occurs through a series of highly regulated steps, which can be followed by a change in expression of the differentiation antigens CD4, CD8, CD25 and CD44. In ascending order of maturity the thymocytes are named DN1 (CD4-, CD8-, CD44+CD25-), DN2 (CD4-, CD8-, CD44+CD25+), DN3 (CD4-, CD8-, CD44-CD25+), DN4 (CD4-, CD8-, CD44-CD25-), DP (CD4+, CD8+), and SP (CD4+ or CD8+). DN1 cells up-regulate CD25 expression coincident with their commitment to the T cell lineage and begin to rearrange their TCRg, d and b genes by a process termed V(D)J recombination. Thymocytes that productively rearrange their TCRg and d genes are eligible to become gd T cells, while rearrangement of the TCRb gene allows expression of the pre-TCR complex and commitment to the ab T lineage. Thymocytes expressing a functional pre-TCR are able to pass a developmental checkpoint called b-selection and progress to the DP stage in a process involving massive proliferation. Once at the DP stage, thymocytes are subjected to positive and negative selection ensuring that only functional and beneficial T cells are allowed to patrol the body. The T Cell Biology group examine the role of the TCR complex in the various developmental checkpoints and lineage choices as well as the molecular mechanisms underlying these events. 

T cell activation

T cell responses are initiated when naïve T cells encounter antigen-presenting cells in the secondary lymphoid organs. When the TCR recognizes foreign antigens, it initiates a wide network of intracellular signalling processes, which are closely regulated by a complicated interplay between post-translational protein modifications (e.g. phosphorylation, de-phosphorylation, ubiquitination) and translocation of the individual signal transducers. The model outlining our current knowledge of the TCR signaling pathway dictates that following TCR ligation the protein tyrosine kinase Lck is activated resulting in phosphorylation of the CD3 chains of the TCR and ZAP70. Activated ZAP70 phosphorylates LAT that subsequently recruits several SH2 domain-containing proteins including PLC-γ1. Activation of PLC-γ1 results in the hydrolysis of IP3 and DAG. IP3 regulates intracellular calcium mobilization and DAG regulates the activation of protein kinase C and RasGRP, an activator of Ras. By contributing to Ras activation, PLC-γ1 indirectly controls the mitogen-activated protein kinase cascades and the ensuing production of transcription factors leading to gene expression and cell-cycle entry. The T Cell Biology group aim to clarify the TCR signalling pathways induced following antigen encounter and to define the impact of these on T cell activation and function.

T cells and inflammation

Inflammation is initiated by a 'danger signals' e.g. UV light, stress or allergens and starts the production of a variety of pro-inflammatory cytokines and chemokines. These are produced by cells from the innate immune response and they are involved in the activation and differentiation of both naïve and memory T cells as well as the recruitment of these cells to the inflammation site. Our focus is skin inflammation. We are primarily investigating this by using contact hypersensitivity (CHS) as a model. CHS is classically thought of as being mediated by Th1 and CTL cells. However, during the last couple of years it has become clear that other cell types from both the innate and the adaptive immune response are important both during the sensitisation and elicitation reactions e.g. keratinocytes and Th17 cells.  Our research areas are the interaction between the innate and adaptive immune response during CHS, how mixtures of allergens affect the inflammatory response, as well as the ability of potent allergens to induce tolerance.