The elderly can't fend off infections as vigorously as they once could. Agius et al. now show that part of the problem—at least in the skin—stems from memory T cells that can't get to their destination.

People have sluggish immune responses as they grow old, so it was of little surprise to Agius and colleagues that lymphocytes didn't rush to the site of antigen injection in the skin of people over 70 years old. What was surprising, however, was that T cells isolated from these individuals were not inherently defective, as they responded normally to in vitro activation.

Instead, it appeared that one of the first steps in the immune response fell short. After antigen injection, macrophages in elderly skin produced less TNF than did those in younger skin. Endothelial cells lining skin vessels in the elderly expressed lower levels of adhesion molecules, which are normally induced by TNF and are required for circulating T cells to migrate into tissues. As senior author Arne Akbar explains, “Road signs that direct T cells to the skin epithelium were missing.”

Previous studies suggested that macrophage responses to TLR ligands wane with age, but Agius and colleagues found no such defect. Instead, suppression of TNF production might be mediated by regulatory T cells, which are known to increase with age and to inhibit TNF secretion by macrophages. Indeed, the skin of the older participants contained more of these cells, both before and after injection. Some researchers have suggested that regulatory T cells accumulate to prevent unnecessary inflammation in response to natural debris that builds up as people grow old. If this is true, speculates Akbar, relevant immune responses could also be blocked, interfering with T cell immunosurveillance and crippling responses to vaccines.