Figure 2.

Activation and differentiation of ApoB-specific CD4⁺ T cells in mice. The ApoB-containing apolipoproteins LDL, VLDL, and chylomicrons (CM) are taken up by antigen-presenting cells (APCs) by endocytosis. After their intracellular processing, apolipoprotein-derived peptides are loaded on MHC-II molecules, before the entire MHC-II-peptide complex is transposed to the cell membrane. There, MHC-II-peptide complexes can be recognized and bound by a specific T cell receptor (TCR). In combination with sufficient co-stimulatory signaling events provided by the APC, a naïve CD4⁺ T cell is activated and may differentiate into distinct, partially overlapping T_H-types of immunity: Most ApoB-specific CD4⁺ T cells (ApoB⁺) express transcriptomes and markers of T_H17 and T-regulatory cells (T_reg). They express CCR5 and CXCR6, two known chemokine receptors (CCRs) required for aortic homing. Over time, ApoB⁺ cells acquire additional pro-inflammatory transcriptional programs and express the T_H1 transcription factor T-bet, as well as the CCRs CXCR5 and CCR6. The initially detectable protective T_reg signature is lost in this process. After vaccination, IL-10 secreting FoxP3⁺ApoB⁺ cells have been described at the site of vaccination. In transgenic mice, only expressing a TCR that recognizes a specific ApoB-peptide, a part of ApoB⁺ cells differentiates into T_FH that promote plasma cells generation and the production of LDL-lowering anti-LDL antibodies.