Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4+ T Cell Responsiveness.

Kim Han,Rebecca D Huffstutler,Tiffany M Powell-Wiley,Komudi Singh,Yvonne Baumer,Michael N Sack,Jinguo Chen,Julián Candia,Foo Cheung,Katherine E R Stagliano,Mehdi Pirooznia,Matthew J Rodman,Shahin Hassanzadeh

doi:10.3390/nu13051492

Abstract

Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects’ blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4+ T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4+ T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4+ T cell immune responsiveness.

Highlights

Caloric restriction, intermittent fasting and time-restricted feeding in animal models [1,2,3,4], in healthy volunteers [5,6,7,8] and in overweight individuals [9] have been found to confer anti-inflammatory effects
A clinical study was performed on peripheral blood mononuclear cells (PBMCs) to compare cellular gene expression profiles in response to an overnight fast (Baseline), to a 24-h fast (Fasting) and in response to 3 h of refeeding (Refed; Supplementary Figure S1A)
The unbiased bioinformatic analysis of the data in the PBMCs supported the results that fasting had a robust effect on CD4+ T cells, the study could not distinguish between cell intrinsic regulatory effects versus paracrine effects on the cells from the 24-h fast [32]

Summary

Introduction

Intermittent fasting and time-restricted feeding in animal models [1,2,3,4], in healthy volunteers [5,6,7,8] and in overweight individuals [9] have been found to confer anti-inflammatory effects. Caloric restriction, mimetic diets and time-controlled fasting reduce inflammatory markers in human disease [10,11,12]. Time-controlled limitation in calories, per se, may evoke the process of hormesis, which, in part, is the concept where a mild, sublethal stress can protect against subsequent excessive stressors [27,28]. This biological phenomenon has been shown where caloric restriction increases resistance to subsequent thermal or oxidative stress injury (reviewed [29]). Data is emerging that macrophage polarization may be modulated by hormetic triggers [13,30]

Methods

Results

Discussion

Conclusion