Figure 5.

Activated and aggressive CD4⁺ T cell soldiers convert to spies. Fully activated T cells programmed to mediate antigen-specific injury can be neutralized or change sides. Five pathways are illustrated, and described from top to bottom. (1) Neutralization or cell death occurs from repeated T cell receptor (TCR) activation and proliferation of effector T cells (pathway 1). The cells can die of exhaustion, leading to clonal pruning. (2) Excessive and repeated stimulation of TCRs on effector cells induces them to express surface molecules that, when they bind ligand, induces apoptosis (pathway 2). This leads to activation induced cell death (AICD). The best described pathways are Fas/FasL and programmed cell death protein-1 (PD1) /programmed cell death protein-1 ligand (PD-L1). (3) Induction of IL-10 expression by effector T cells (pathway 3). After repeated stimulation and expansion, activated effector T cells can be induced to express IL-10 usually by IL-27 binding to IL-27R. The release of IL-10 by these effector T cells reduces inflammation, especially the activation of APCs. The last two pathways involve T regulatory cells (Tregs) infection of effector T cells to convert them to Tregs. Direct contact with activated Tregs can infect effector T cells to make them regulatory. (4) TGF-β on Treg surface can, by cell-cell contact, induce FOXP3 and endow Treg function in effector T cells (pathway 4). (5) IL-35 released from activated Tregs binds the IL-35 receptor on activated T cells and converts them into FOXP3⁻ iTr35 cells (pathway 5). AICD, activation induced cell death.