The Effects of TLR Activation on T-Cell Development and Differentiation

Figure 3

Peripheral T-cell tolerance in lymph node. All the subsets of LNSC can express PTA. AIRE and Deaf1 are involved in the regulation of this expression. Both the LNSC and follicular DC in lymph node can serve as APC to present or cross-present self-epitopes to T cells. Lymph contains abundant-processed protein fragments and peptides from draining organs or tissues and serves as a significant pool of self-antigen for the induction of peripheral tolerance. LNSC can upregulate co-stimulatory molecules to induce T-cell lineage deletion. The autoreactive T-cell lineage deletion is mediated by apoptosis mediated by Fas or Bim signals when inflammation is absent. The engagement of Fas ligand with Fas on T-cell surface triggers the apoptosis of activated T cell through caspase-dependent pathway. T-cell stimulation causes downregulation of Bcl-2 and a transient slight upregulation of Bim and this results in increased uncomplex Bim which is combined with Bcl-2 in resting status. This then activates Bcl-2 homologous antagonist/killer (Bak) and Bcl-2–associated X protein (Bax). Consequently, the integrity of mitochondria is damaged and this culminates in cell death. The tolerogenic DCs induce T-cell functional tolerance, that is, anergy by upregulation of either CTLA-4 or PD-1 expression in T cells. Augmented expression of CTLA-4 can block co-stimulatory signals by binding to CD80/86 in competition with CD28 to induce T-cell anergy. In recognition of self-antigen, PD-L1 on tolerogenic DCs interacts with PD-1 on T cells to limit T-cell activity in peripheral tissues and maintain T cell in unresponsiveness. PD-1 suppresses the PI3K induction and Akt activation. This disturbs cellular glucose metabolism and impairs T-cell survival. PD-1 activation also inhibits the cell-survival factor Bcl-xL production. CTLA-4 engagement blocks Akt phosphorylation by activation of protein phosphatase 2. Engagement of both PD-1 and CTLA-4 can significantly decrease gene transcriptions of T cell being activated.