Increased Plasticity of FOXP3+ Treg under Pathological Conditions Convert Treg into Either Novel Treg or Th1‐Treg
Authors: Xu Keman , Yang William Y. , Nanayakkara Gayani K. , Shao Ying , Yang Fan , Hu Wenhui , Choi Eric T. , Wang Hong , Yang Xiaofeng 
Published: June 2021

Naïve CD4+ Th (T helper cells) can differentiate/be polarized in to 9 terminally differentiated Th cell subsets depending on the cytokine repertoire and anatomical location. CD4+ FOXP3+ (forkhead box P3) regulatory T cells (Treg) are one of the Th subsets. Treg are well known to suppress immuno‐pathological reactions in host immune system against antigens and dangers. Recently we proposed a novel concept, which suggested that pathological conditions re‐shape physiological Treg into pathological Treg that have weakened immuno‐suppressive functions and show increased plasticity. This was substantiated by several reports by demonstrating that there are endogenous mechanisms available to suppress Treg under various pathologies. Furthermore, Th1 like–Treg and Th17 like–Treg have also been reported. However, a comprehensive analysis was not conducted to identify whether Treg can convert into other immune cell types such as APCs (antigen presenting cells) when given the right condition. To test this hypothesis, we conducted an extensive experimental datamining approach. In our study, we analyzed the tissue expression patterns of as many as 61 Th subset regulators in physiological and pathological conditions. Our analysis revealed the following findings. 1) All the Th subset regulators are differentially expressed in various human tissues including heart and vascular tissues at physiological conditions. 2) Chronic metabolic diseases and autoimmune diseases increase multiple Th subset regulators but decrease Treg regulators. Familial hypercholesterolemia and lupus do not increase Th1 regulators. 3) Severe trauma increases Th2, Th9, Tfh, and Th17 subset regulators but decreases Th1 and Treg regulators in blood. In contrast, burn injury decreases all Th subset regulators except Th22 regulators. 4) Vascular cells are functional as innate immune cells, express numerous Th subsets‐promoting cytokines and induce Th regulator expression except the regulators for Treg. 5) Gata3 and Hdac6 promote, but Bcl6 inhibits, Th subset regulator expression in Treg, and regulate Treg plasticity and heterogeneity. 6) Gata3 and Bcl6 inhibit the expression of MHC class II, and T cell co‐signaling receptors in Treg; and consequently mutations of Gata3 and Bcl6 “trans‐differentiate” Treg into APC‐like Treg. Based on our findings, we conclude that increased plasticity of naïve T‐reg under pathological conditions with decreased expression of Gata3 and Bcl6 can upregulate MHC class II molecules and T cell co‐stimulation receptors expression that subsequently convert them to APC like‐Treg. Furthermore, our data suggested that Th subset may have various non‐immune activities as well. Our findings provide novel insights into Th subsets and Treg, which may lead to future development of novel therapeutics for the treatment of inflammation, cancers, transplantation, autoimmune diseases and tissue regeneration.Support or Funding InformationRO1‐HL132399‐01A1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.