Naringenin modifies the development of lineage-specific effector CD4+ T cells

Authors: WANG, JUNPENG - Henan University; XINLI, NIU - Henan University; WU, CHUNFANG - Henan University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Frontiers in Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/2018
Publication Date: 10/1/2018
Citation: Wang, J., Xinli, N., Wu, C., Wu, D. 2018. Naringenin modifies the development of lineage-specific effector CD4+ T cells. Frontiers in Immunology. 9:2267. https://doi.org/10.3389/fimmu.2018.02267.
DOI: https://doi.org/10.3389/fimmu.2018.02267

Interpretive Summary: In our previous study we found that dietary supplementation with naringenin, a substance most abundant in citrus fruits, diminished the effects of experimental autoimmune encephalomyelitis, a rodent model for human multiple sclerosis. It is not clear whether naringenin directly affects the process through which common precursor T cells demonstrate different functions. Obtaining such information is important for understanding the working mechanisms underlying the naringenin's protective effect in autoimmune diseases. Our results showed that naringenin had a direct effect on T cells turning into anti-inflammatory types while prohibiting their development toward pro-inflammatory types. This is the first direct evidence for the influence of naringenin on T cell differentiation. Our results have expanded our understanding for naringenin's working mechanisms in T cell-mediated immune disorders, and the information obtained may help develop more specific dietary strategies in preventing and alleviating T cell-mediated autoimmune diseases.

Technical Abstract: Disrupted balance in the lineages of CD4+ T cell subsets, including pro-inflammatory T helper (Th) cells and anti-inflammatory regulatory T cells (Treg), is a primary pathogenic factor for developing autoimmunity. We have found that this immunomodulatory effect of naringenin on effector T cells and T-cell mediated experimental autoimmune encephalomyelitis. We therefore explored the effects of naringenin on the development of different effector CD4+ T cells. Naive CD4+ T cells were differentiated under respective Th1, Th2, Th17, and Treg polarizing conditions with naringenin. Percent populations of each differentiated CD4+ T cell subsets were determined and the corresponding regulating pathways were investigated as underlying mechanisms. Naringenin mainly inhibited CD4+ T cell proliferation and differentiation to Th1 and Th17, but did not affect Th2 cells. Impeded Th1 polarization was associated with inhibition of its specific regulator proteins T-bet, p-STAT1 and p-STAT4 by naringenin. Likewise, Th17 regulator proteins ROR gamma t, p-STAT3 and Ac-STAT3 were also inhibited by naringenin. In addition, naringenin promoted Treg polarization and also prevented IL-6-induced suppression of Treg development via down-regulation of p-Smad2/3 as well as inhibition of IL-6 signaling, and the latter was further supported by the in vivo results showing lower soluble IL-6R but higher soluble gp130 levels in plasma of naringenin-fed compared to the control EAE mice. Naringenin impacts CD4+ T cell differentiation in a manner that would explain its beneficial effect in preventing/mitigating T cell-mediated autoimmunity.