Agrawal, T; (2018) Epithelial ErbB2 regulation of thymus homeostasis and age-associated T cell mediated immunity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The molecular mechanisms governing the functional and structural decline of thymus with age, causing thymic immunosenescence, are incompletely identified. Using a bitransgenic mouse model, Dr Giangreco discovered that the over-expression of receptor tyrosine kinase ErbB2 causes reversible thymic atrophy. The over-expression of epithelial ErbB2 upon doxycycline administration in bitransgenic mice led to decreased thymus size and cellularity, loss of cortical-medullary boundary and abnormal T cell differentiation, bearing similarity to age-dependent thymic involution. This thesis set out to investigate this observation in more detail. I demonstrated that the observed atrophy in bitransgenic thymuses was because of thymus-specific ErbB2 expression, by employing foetal thymic organ cultures. In addition, I showed that over-expression of epithelial ErbB2 disrupted the thymic epithelial cells distribution. Also, an increase in Sca1+Cd49f+ epithelial cells with stem cell potential was noted, explaining why the thymic atrophy in bitransgenic mice was reversible. Exploration of the potential mechanistic pathways found that the thymic atrophy phenotype of K14-NICDER mice, in which epithelial Notch is activated upon tamoxifen administration, resembled the bitransgenic mouse thymic atrophy phenotype. However, mechanistic studies failed to establish ErbB2 acting upstream of Notch, and require further investigation. Administration of Lapatinib, an ErbB2 inhibitor improved the thymic organization and function in aged mice. Lapatinib treatment of aged mice also enhanced vaccine responses to Prevenar 13, a Streptococcus pneumoniae glycoconjugate vaccine, and increased the efficacy of vaccination to protect against subsequent pneumonia challenge. However my results showed that ErbB2 inhibition does not reverse thymic atrophy in scurfy mice, which have truncated Foxp3 protein, and an autoimmune phenotype. In conclusion, this study highlights the importance of ErbB2 in maintaining thymus homeostasis and thymus mediated immunity, and proposes a novel ErbB2 inhibition therapy for rejuvenating an aged thymus, to counter the associated immunosenescence and thereby improve vaccine responses.

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