Using a new form of microscopy to penetrate living lymph nodes, UCSF scientists have for the first time viewed immune cells at work, helping clarify how T cells control autoimmunity.
The technique, known as two-photon laser-scanning microscopy, was able to focus deep within the lymph node of a diabetic mouse, allowing the researchers to show that immune cells known as T regulatory, or Treg, cells control the destructive action of rogue autoimmune cells when each of the two cell types interact with a third kind of cell.
The role of the third cell type — the antigen-presenting dendritic cell — in preventing autoimmune attacks of healthy tissue has been a focus of intense research over the last 15 years. The new study supports one contending hypothesis: It is not the interaction between the two types of T cells, but rather the interaction of each with the dendritic cells that leads to protection from autoimmune assaults.
The scientists used fluorescent dye to mark different types of cells so they could directly observe the interactions of the key cell types involved in initiating autoimmune attacks and the control of their actions by therapeutic regulatory T cells.
The team of immunologists and diabetes researchers used the new microscope to show that when Treg cells are absent, the potentially destructive autoreactive T cells, known as T helper cells, swarm around the dendritic cells where they are primed to attack the body’s own tissue — the cause of type 1 diabetes, arthritis and other autoimmune diseases.
Immunologists have long sought to harness the potent immunosuppressive properties of the regulatory T cells to treat autoimmune diseases and organ transplant rejection. By pinpointing where and how regulatory T cells work in vivo in mouse models, the researchers hope to better adapt the regulatory T cells for therapeutic use in the future. For example, Tang said, one can imagine that at the early stage of an autoimmune attack, it may be very helpful to direct the therapeutic regulatory T cells to the lymph nodes so they interact with dendritic cells before the autoimmune T cells are able to, and thereby “stamp out the initial sparks” before the disease spreads to the tissue.
Krummel notes that the research dispels some assumptions about cellular movement and interaction. Many had assumed that T cells move very little inside the lymph node. The video microscopy shows that they move about one body length per minute, and that much of the movement is quite directed, for example toward the dendritic cells, rather than random activity. These directed movements are followed by prolonged interaction between autoimmune T cells and dendritic cells that lead to proliferation of autoimmune cells and eventually tissue destruction.