Quality control–the removal of immune cells that have the ability to attack our own tissues–is a central tenet of the immune system. In type 1 diabetes (T1D), impaired quality control in the thymus, leads to release of beta cell–reactive immune cells (called T cells) into the blood; such cells facilitate destruction of insulin–producing beta cells in the pancreas. Little is known how thymic quality control fails.
Medullary thymic epithelial cells (mTECs) are specialized cells in the thymus that are critical for expressing a range of self–proteins, including beta cell proteins e.g. insulin, to developing T cells enabling selection and destruction of T cells reactive to the host proteins. Loss, or impairment, in mTEC homeostasis or function leads to autoimmune conditions in mice and humans. Previously in NOD mice, a well–described animal model of T1D, we made a breakthrough in understanding why thymic quality control fails; abnormal structures enriched with immune cells called thymic B cells form, autoantibodies bind to mTECs and insulin–expressing mTECs die. Now we know that mTEC survival is linked to activation of intracellular complement component C3 (termed complosome) in mTECs, and there is an undefined relationship between thymic B cells, mTEC complosome activity and mTEC survival. We have initiated translation of our findings to humans; human mTECs express C3 from fetal to adult life correlating with an increase in thymic B cells, and complosome activity is detectable in human thymic tissue sourced from non–diabetic donors. In stage 1 of this project, using a multiplexing immunhistochemical approach we will determine if beta cell–specific protein expression and mTEC survival is linked to impaired C3/complosome activity in nPOD donors without diabetes at various ages and in both males and females. In Stage 2, we will expand the number of ND donors and determine if these characteristics are altered in AAb+ and T1D donors. Further, we will analyse thymic B cells(number, location and phenotype),to determine if ‘rogue’ thymic B cells correlate with T1D development.
