Mice whose scout immune cells get stuck in organs grow lymph-node-like clusters, and a drug against senescent cells keeps the clusters from forming, according to a Genentech preprint

Mice whose scout immune cells get stuck in organs grow lymph-node-like clusters, and a drug against senescent cells keeps the clusters from forming, according to a Genentech preprint

On October 11, Genentech researchers posted a preprint on bioRxiv, which is a manuscript that has not yet been peer reviewed. Dendritic cells work as scouts: they collect samples of foreign material in tissues, carry them to a lymph node and present them to T cells.

With age, clusters of T and B cells appear in the organs of humans and mice, and some of these clusters are organized like a lymph node. In cancer and chronic inflammation, such clusters can strengthen the immune response. Age-related clusters have been described in the kidneys and liver, but the authors say it is unclear where they come from and what they do.

Tissues from people over 70 contain more of these clusters than tissues from people under 50. Nearly all mature dendritic cells, which are the cells ready to leave for a lymph node, sit inside the clusters. The receptor CCR7 guides cells to the lymph node, and the mouse experiments the authors cite show that with age the cells' ability to follow this signal falls by about half. Which comes first? Either the lingering cells assemble a cluster, or they settle into a cluster that already exists.

To test the first possibility, the authors switched off CCR7 only in the classical dendritic cells of mice, because losing the receptor throughout the body causes autoimmune disease. The cells stayed in the tissues, and by 3–4 months healthy organs had developed clusters with blood vessels and signaling proteins like those of a lymph node. These clusters formed without tissue damage and without antibodies against the animals' own cells. In ordinary mice, clusters appear later and are less pronounced. Clusters formed even when only half of the dendritic cells lost the receptor, which is how the authors model the decline that comes with age.

When the authors removed dendritic cells for a week from mice lacking CCR7, the established clusters dissolved. A protein that increases the number of dendritic cells also induced clusters in ordinary mice, but after the protein was withdrawn these clusters mostly resolved, whereas in mice lacking CCR7 they persisted. The authors conclude that a temporary excess of dendritic cells is enough to start a cluster, and that the cells must be present continuously to maintain it.

Because clusters in mice lacking CCR7 appear only with age, the authors tested whether cellular senescence plays a role. Senescent cells stop dividing and release signaling substances. The combination of dasatinib and quercetin kills senescent cells. In two-month-old mice lacking CCR7, it reduced cluster formation, but it did not dissolve clusters that had already formed in adult mice. In culture, senescent connective tissue cells shifted dendritic cells toward the state that anti-inflammatory substances induce. In the authors' model, aged tissue gives dendritic cells anti-inflammatory traits in this way, and their retention in the tissue lets them organize a cluster.

Inside the clusters of mice lacking CCR7, the proportion of regulatory T cells, which dampen the immune response, is higher than in ordinary mice. In colitis induced by dextran sulfate, these mice at first lost weight just as ordinary mice did, but their gut already held more regulatory T cells at that stage. After the compound was withdrawn, they recovered better: the gut shortened less and showed less inflammation and fewer ulcers.

In mice with lung cancer, a study in Science found that early formation of these structures requires dendritic cells to travel to the lymph node nearest the tumor. In the present work, retention of dendritic cells speeds formation instead. The authors propose that age-related clusters are "an organized immune adaptation that arises to promote tissue tolerance and protection in aged tissues" (tolerance here means the immune system's acceptance of the body's own tissues). In their view, treatments aimed at dendritic cells could make it possible to dampen local inflammation in chronic inflammatory diseases, autoimmunity and organ transplantation.