Searching for the missing T Cell Receptor (TCR) in Anaplastic Large Cell Lymphoma (ALCL): Surplus to requirements or a protagonist in lymphomagenesis?
Fairbairn, Camilla Jayne
University of Cambridge
Doctor of Philosophy (PhD)
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Fairbairn, C. J. (2018). Searching for the missing T Cell Receptor (TCR) in Anaplastic Large Cell Lymphoma (ALCL): Surplus to requirements or a protagonist in lymphomagenesis? (Doctoral thesis). https://doi.org/10.17863/CAM.20257
Anaplastic Large Cell Lymphoma (ALCL) is a peripheral T cell lymphoma divided into three distinct entities: ALCL, Anaplastic Lymphoma Kinase (ALK)+, ALCL ALK- and cutaneous ALCL. In the majority of ALCL, ALK+, ALK is expressed as the result of a chromosomal translocation generating Nucleophosmin 1(NPM)-ALK, which is considered the main driver. ALCL have an unusual immunophenotype; they rarely express a T cell receptor (TCR), but are often positive for CD4 and produce cytotoxic proteins such as perforin and Granzyme B, but in the absence of CD8, questioning the origin and pathogenesis of this malignancy. Expression of NPM-ALK in mice from the T-cell specific CD4 promoter gives rise to thymic lymphomas not modelling human ALCL suggesting that other events and/or expression of NPM-ALK at a defined stage of T cell ontogeny is required for peripheral T cell lymphoma development. Indeed, back-crossing the CD4/NPM-ALK line onto a RAG competent, MHC class I restricted ovalbumin-specific TCR, OTI transgenic line (CD4/NPM-ALK/OTI) permits peripheral lymphoma development mimicking human ALCL (but CD4/NPM-ALK/OTII mice still develop thymic lymphoma); tumours contain cells histopathologically identical to ALCL hallmark cells. Interestingly, peripheral tumours developing in this model also lack cell surface expression of the OTI TCR in fitting with observations of a lack of TCR expression on human ALCL. It follows that stimulation of T cells in vivo by infection with MHV-ova prevents lymphomagenesis suggesting that the TCR is detrimental to tumour growth. Indeed, strong stimulation via the TCR of NPM-ALK-expressing primary T cells in vitro, impedes cell proliferation but cell growth is favoured when a weaker stimulus is employed. Overall, data presented in this thesis identifies a potential mechanism of lymphomagenesis accounting for the unusual immunophenotype of ALCL and an explanation as to why cells lack a TCR and associated proximal signaling.
Analplastic Large Cell Lymphoma, T Cell, Lyphoma, T Cell Receptor, T Cell Signaling
This record's DOI: https://doi.org/10.17863/CAM.20257