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

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.

Association of Periodic Fasting with Lower Severity of COVID-19 Outcomes in the SARS-CoV-2 Pre-Vaccine Era: An Observational Cohort from the INSPIRE Registry

“…Routine periodic fasting was associated with a lower risk of hospitalization or mortality in patients with COVID-19. While fasting is not a panacea or a quick fix for health problems, low-frequency fasting improves cardiometabolic health even without significant weight loss,(18,31) and multiple biological mechanisms (4-8,11,12,24-28,30) and epidemiologic results (13-15,19,20) support the idea that consistent fasting may limit COVID-19 severity. Fasting may do so via acute but temporary physiological changes during energy deprivation and by persistent modification of basal physiological norms and reduction of chronic disease risks across repeated fasting episodes.…”

“…(24) While that finding requires testing in humans, other evidence supports the activation of general immune responses and autophagy by fasting. (25,26) Interestingly, small human studies reveal that intermittent fasting blunts CD4 + T-cell responsiveness during fasting by upregulating insulin-like growth factor binding protein 1 and FOXO4/FK506-binding protein 5,(27,28) and that fasting generally suppresses the production of pro-inflammatory cytokines. (25) Often in severe COVID-19 the human immune system over-reacts to SARS-CoV-2 infection and the consequent hyperinflammation can result in respiratory failure.…”

Association of periodic fasting with lower severity of COVID-19 outcomes in the SARS-CoV-2 prevaccine era: an observational cohort from the INSPIRE registry

“…Routine periodic fasting was associated with a lower risk of hospitalisation or mortality in patients with COVID-19. While fasting is not a panacea or a quick fix for health problems, low-frequency fasting improves cardiometabolic health even without significant weight loss,18 32 and multiple biological mechanisms4–8 11 12 24–28 30 31 33 and epidemiological results13–15 19 20 support the idea that consistent fasting may limit COVID-19 severity. Fasting may do so via acute but temporary physiological changes during energy deprivation and by persistent modification of basal physiological norms and reduction of chronic disease risks across repeated fasting episodes.…”

“…While that finding requires testing in humans, other evidence supports the activation of general immune responses and autophagy by fasting 25 26. Interestingly, small human studies reveal that intermittent fasting blunts CD4 + T cell responsiveness during fasting by upregulating insulin-like growth factor binding protein 1 and FOXO4/FK506-binding protein 5,27 28 and that fasting generally suppresses the production of proinflammatory cytokines 25. Often in severe COVID-19 the human immune system over-reacts to SARS-CoV-2 infection and the consequent hyperinflammation can result in respiratory failure 29.…”

m6A regulator–mediated RNA methylation modification patterns and immune microenvironment infiltration characterization in patients with intracranial aneurysms

“…m6A is the most common form of mRNA modifications in eukaryotes and functionally regulates the eukaryotic transcriptome (37), which affects mRNA splicing, export, localization, translation, and stability (38). There has been a large amount of evidence to support the view that m6A methylation modifications perform an instrumental role in the onset and progression of a variety of illnesses, including malignant tumors (39). Nevertheless, there is a scarcity of studies on m6A methylation in IA.…”