Fat-loving Tregs control insulin sensitivity during ageing

I have noticed in the past couple of weeks that there is a surge of Foxp3⁺ T cell papers published in top journals. Just yesterday Nature published another paper where the authors claim that they have discovered ageing-related [separate] pathway of insulin resistance driven by fat-associated Tregs.

Lets review their claims. First, the authors showed that unlike "classical" obesity-driven insulin resistance, ageing-related insulin resistance is characterized by enrichment of Foxp3⁺ T cells in adipose tissue (visceral adipose tissue, VAT).

Next, the authors showed that selective depletion of fat Tregs in ageing Foxp3^cre PPARγ ^fl/fl mice promoted shift into "lean body" metabolism[selective decrease in fat mass].

This shift to lean body metabolism in fat Treg depleted mice [i.e. insulin sensitivity ↑] occurred in ageing mice, not in young or obese mice.

Finally, since most of fat Tregs were positive for surface ST2, a receptor for IL-33, their depletion in ageing mice with anti-ST2 antibody [not very efficient by the way] could still improve insulin sensitivity by 25% over control [without any overt inflammation].

In summary, this study uncovered a novel pathway of ageing-associated insulin resistance driven by ST2⁺ fat Tregs. This pathway differs from obesity-driven insulin resistance. However, it is important to remember here that B6 mice [used in this experiments] have strong tendency for obesity during ageing and it remains seen whether this phenomenon with fat Tregs will be applicable for other strains or for humans.

David Usharauli

Serum level of β2-microglobulin, a component of HLA class I system, may predict age-related decline in cognitive function

Ageing-associated decline, especially cognitive decline, is a social-medical condition that would directly affect overall societal wellbeing. It is still widely unmet biomedical challenge. In general, medical conditions related to brain functions are the least understood topics in medicine.

Recently journal Nature Medicine has published an article suggesting that high level of β2-microglobulin, a component of immune system class I antigen-presentation pathway, correlated to cognitive decline during ageing.

These is a mouse study. Now, this is a big caveat. In addition, though the authors believe they studied "cognitive" function in mice, the actual experiments, in my view, are based more on mouse locomotor skills.         

Initially, the authors reported that both in mice or humans ageing correlated with increased level of β2-microglobulin in the circulation.

Next, the authors showed that young 3 months old mice intravenously injected with β2-microglobulin made more errors in tasks requiring locomotor skills (water maze and fear freeze).

Interestingly, this negative effect of exogenous β2-microglobulin on mouse locomotive skills were short-lived (< 30 days, see d).

Importantly, β2-microglobulin-injected young TAP1 KO mice that lack surface MHC class I molecules did not show decline in their  locomotive skills.

Finally, old (17 months) β2-microglobulin KO mice showed less errors in their locomotive skills compared to their wild-type littermates.

In summary, this study claims that increase in β2-microglobulin level may indicate in locomotive skills in mice. Now, there are some major weakness in this paper that could affect its validity: (1) β2-microglobulin is a ~12kD size molecule that would have hard time to cross brain blood barrier (BBB); (2) there is substantial overlap between baseline and experimental errors in young mice in different figures (compare Fig. 1e vs. Fig. 2c vs. Fig. 4a); (3) outcome of experiments with β2-microglobulin injection into young β2-microglobulin KO are not done or not shown. 

David Usharauli