Seeding of visceral adipose tissue with perinatally generated regulatory T cells shapes the metabolic tenor in mice

The Foxp3⁺CD4⁺ regulatory T cells (Tregs) generated around birth are phenotypically and functionally distinct from those engendered during adulthood. That perinatally produced Tregs persist for a protracted period in peripheral lymphoid organs has been well documented, as has their superior ability to protect the organism from many autoimmune diseases. However, their contribution to pools of nonlymphoid-tissue Tregs and their homeostatic functions therein have been little studied. We show that perinatal Tregs preferentially derive from a CD25⁺Foxp3^- thymocyte progenitor; that they seed and persist to varying degrees in every nonlymphoid tissue examined; and that transient depletion of perinatally generated Tregs in adults, but not in neonates, is followed by poor reconstitution of Treg numbers and phenotypes in epididymal visceral-adipose tissue (eVAT) and the skin but not in several lymphoid and other nonlymphoid tissues. Potential clinical implications of such a deficiency are highlighted by findings on mice subjected to weight cycling: Imposing a low-fat-high-fat-low-fat diet regimen in adult, but not juvenile, mice results in an impoverished eVAT, but not spleen, Treg compartment, accompanied by normal weight gain and glucose tolerance but profound insulin resistance. These findings point to a layered immune system, the different layers exerting specialized, nonredundant functions.