Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

The immune system is highly organized and multifunctional; it
protects the organism against invading pathogens (immune response),
while at the same time being tolerant to ‘self’ (immune tolerance).
Central tolerance is achieved during T-cell development by negative
selection via self-peptide-MHC complexes (pMHC) presented by thymic
dendritic cells (tDCs) and medullary thymic epithelial cells
(mTECs). However, how self-antigens are processed into peptides
that further are shuttled onto major histocompatibility complex
(MHC) class II in thymic epithelial cells (TECs) is not fully
understood. One candidate pathway involved in this process is
macroautophagy (referred to as autophagy hereafter), originally
thought to solely be involved cellular housekeeping, has previously
been implicated to contribute to MHC class II endogenous antigen
presentation by TECs. This research project investigates the role
of autophagy in negative selection by TECs. A model antigen was
targeted specifically to the autophagosome in autoimmune regulator
(Aire)+ mTECs. Transgenic mice expressing this antigen were
generated. Experimental data indicated that the efficient direct
presentation of this endogenous antigen by mTECs observed in vitro
was sufficient to induce negative selection in vivo. By contrast,
interference with autophagosomal processing of this antigen through
exchange of one amino acid or disruption of an essential autophagy
gene abolished endogenous antigen presentation by mTECs and
impaired negative selection, which resulted in the escape of
autoreactive CD4 T-cells. Moreover, further investigation showed
that if the level of antigen expression was limited,
autophagy-dependent direct presentation by mTECs was essential for
T-cell deletion, while with sufficient amounts of antigen provided
by mTECs, direct presentation by mTECs and indirect presentation by
tDCs co-operated to induce central CD4 T-cell tolerance. These
findings strongly suggest that the autophagy pathway contributes to
CD4 T-cell tolerance induction by facilitating the loading of
intracellular antigens onto MHC class II in mTECs.