Cross-Tolerance and Autoimmunity as Missing Links in Abiotic and Biotic Stress Responses in Plants: A Perspective toward Secondary Metabolic Engineering

Plants employ a diversified array of defense activities when they encounter stress. Continuous activation of defense pathways that were induced by mutation or altered expression of disease resistance genes and mRNA surveillance mechanisms develop abnormal phenotypes. These plants show continuous defense genes’ expression, reduced growth, and also manifest tissue damage by apoptosis. These macroscopic abrasions appear even in the absence of the pathogen and can be attributed to a condition known as autoimmunity. The question is whether it is possible to develop an autoimmune mutant that does not fetch yield and growth penalty and provides enhanced protection against various biotic and abiotic stresses via secondary metabolic pathways’ engineering. This review is a discussion about the common stress-fighting mechanisms, how the concept of cross-tolerance instigates propitious or protective autoimmunity, and how it can be achieved by engineering secondary metabolic pathways.

Abstract 44: Failure of Protective Autoimmunity in Mouse and Human Atherosclerosis

Background: In atherosclerosis, CD4 + T helper cells recognize auto-antigens including ApoB, the main protein in low-density lipoprotein (LDL). However, atherosclerosis-specific, auto-reactive CD4 + T cells have not been detected in vivo , and their function is unknown. Methods and Results: We have previously identified peptides derived from mouse ApoB that bind with high affinity to the MHC class II molecule of C57BL/6 mice (I-A b ). We designed and validated a new multimer of a recombinant MHC-II molecule fused to one ApoB auto-epitopes, P6 (TGAYSNASSTESASY, P6:I-A b ), that enabled detection of low-affinity, P6-reactive CD4 + T cells. Using this P6:I-A b multimer, we identified ApoB-reactive CD4 + T cells in healthy, young C57BL/6 mice that were predominately differentiated T-regulatory cells (T regs ) and expressed IL-10, a known atheroprotective cytokine. This population was detectable in lymph nodes and already showed a memory phenotype in young animals without atherosclerosis. In Apoe -/- mice, adoptively transferred ApoB P6-specific T regs accumulated in the aorta and draining lymph nodes and gave rise to pathogenic T H 1 and T H 17 cells. This phenotypic switch was caused by enhanced plasticity of antigen-specific T regs as evidenced by multiple clusters of intermediate T reg -T eff phenotypes in single cell RNA sequencing of 4485 antigen-specific CD4 + T cells. In the plaque, many T cells were ex-T regs as identified by a FoxP3 lineage tracker mouse, suggesting that atherosclerosis-specific CD4 + T cells lost their regulatory capacity. Vaccination with P6 maintained a protective phenotype in antigen-specific T regs and protected from atherosclerosis. In humans, ApoB-specific CD4 + T cells from atherosclerotic patients showed the same cytokine patterns found in mouse CD4 + T cells, suggesting that autoimmunity to ApoB is protective first, but later gives rise to a pathogenic CD4 + T cell response that aggravates atherosclerosis. Conclusion: Protective T-regulatory cells recognizing peptide antigens of ApoB exist in naïve mice, protect against atherosclerosis, but convert into pathogenic T H 1 and -17 cells during the natural course of disease in mice and humans. These results call for immunomodulatory therapies to maintain protective autoimmunity.