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Title: The role of Lck in peripheral T cell responses
Author: Qureshi, I. F.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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The signalling mechanisms that control differentiation of naive T cells to effector and memory cells are unclear. A key event in T cell activation by antigen is the phosphorylation of tyrosine based activation motifs in the TCR CD3 complex by the Src-family kinases, Lck and Fyn. Elucidating the exact signalling mechanisms involved in the generation of memory T cells and effector function is fundamental and has important implications particularly in therapeutics, such as in developing treatments for diseases and infection. Lck knockout mice have no T cells, and so we were unable to study the role of Lck in the peripheral T cell compartment. Using mice that express an inducible Lck transgene in T cells, which were bred to the class I MHC restricted F5 TCR transgenic line, we have investigated the role of Lck-mediated TCR signaling in antigen-specific CD8 T cell responses. Stimulation of lymphocytes in vitro showed that the response of F5 T cells to peptide is 10-100 fold less sensitive in the absence of Lck, suggesting that the threshold of triggering is raised, however once cells were activated they underwent a similar program of division. Using an in vivo model where F5 T cells are transferred with flu virus into Rag1"A recipients, we demonstrated that Lck is required for the activation and subsequent generation of functional effector F5 CD8 T cells. The ability to generate functional Cytotoxic T lymphocytes (CTL) was impaired, shown by the reduced killing of target cells in vitro and in vivo. We have also shown defects in the production of IL-2, TNFct and Granzyme B, which appear to be Lck dependent. However there is a less stringent requirement for Lck in the production of IFNy, showing varying levels of Lck requirement for eliciting effector function. In summary we have shown that Lck contributes to multiple stages of memory cell formation. It is required for the priming, expansion and differentiation of F5 CD8 memory T cells, but is not required for their survival.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available