Immune Cell Clustering Suppresses Autoimmunity in Healthy Tissues

In a new study in mice, NIAID researchers describe how regulatory immune cells help suppress autoimmunity by forming clusters around "self-reactive" immune cells—those primed to mount an immune response against the body's own cells and tissues. Their findings reveal that self-reactive immune T cells are activated on a regular basis, and regulatory cells cluster around them to suppress autoimmune responses and limit tissue damage. These insights increase understanding of how healthy tissues work to contain autoimmunity. The investigators report their results in the Nov. 25, 2015, online issue of Nature.

Autoimmunity and Immune Tolerance

Autoimmunity—an immune response to one's own body—occurs to some extent in all people. Self-reactive immune cells generally are eliminated during their development in the bone marrow or thymus, but a few escape into the blood. The body has several checkpoints in place to limit autoimmune responses against the body's own organs, tissues, and cells and to minimize harm.

Regulatory T cells, or Tregs, play an important role in maintaining immune tolerance, the prevention of immune responses against self. Tregs monitor and inhibit the activity of other T cells. However, scientists know relatively little about how Tregs work to contain autoimmune responses in healthy tissues—for example, whether they prevent activation of self-reactive immune cells or primarily limit damage from already-activated cells.

Insights Into Autoimmunity and Autoimmune Diseases

The new findings reveal that Tregs act to limit damage from activated self-reactive T cells present in healthy tissues in mice. Continual activation of self-reactive T cells may account for rapid onset of autoimmune disease when Tregs are not present or are rendered ineffective. The study results also highlight the importance of spatial proximity of regulatory and effector cells in containing autoimmune responses.

Cell Clustering Enforces Immune Tolerance

To explore the role of Tregs in preventing damaging autoimmune responses, Zhiduo Liu, Ph.D., and Ronald Germain, M.D., Ph.D., of the NIAID Laboratory of Systems Biology led a team of scientists to use histo-cytometry, a microscopy technique that tracks cells in tissues, to monitor Tregs and other immune cells in lymphoid tissues from healthy mice.

The researchers found that Tregs forming small clusters produce a signal inside the cell called pSTAT5. They detected a different type of T cell, producing a protein called IL-2, at the center of many of the clusters. IL-2 was responsible for generating the pSTAT5 signal in the Tregs. The clusters also contained dendritic cells, a type of antigen-presenting cell responsible for processing large molecules into fragments, or antigens, which can be recognized by T cells.

Clusters of Tregs (green) form in healthy mouse lymph nodes.

Further experiments suggested that the IL-2-producing T cells were activated by self-antigens presented by the dendritic cells. These activated self-reactive T cells, also known as effector T cells, have the potential to cause tissue damage. The investigators found that Tregs within the clusters produced high levels of inhibitory signals that block the action of the self-reactive cells, preventing harmful autoimmune responses.

The investigators also identified an important role for T cell receptors (TCRs) on the surface of Tregs. Their findings suggest that TCR signaling helps promote clustering of Tregs and encourages them to suppress autoimmune responses. Loss of TCR signaling was linked to enhanced IL-2 production and signaling among effector T cells. In addition, the researchers observed that IL-2 plays a key role in informing Tregs of incipient autoimmune responses, stimulating them to produce pSTAT5 and increasing their capacity to suppress autoimmunity.

Reference

Liu Z, Gerner MY, van Panhuys N, Levine AG, Rudensky AY, Germain RN. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature DOI: 10.1038/nature16169 (2015).