Anatomy of tolerance

The mechanisms of tolerance induction and maintenance remain incompletely understood and have yet to be translated to clinical practice. Advances in imaging techniques have allowed precise examination of cell interactions in the lymph node, often in real time. Herein we review evidence that lymph node structure is dynamic and controls the character of the immune response in a multistep, multiplayer dance. T-cell responses in particular can be initiated or influenced in regions beyond the canonical T-cell zone. We propose that the cortical ridge is one such region required for induction and maintenance of tolerance.

Lymph node domains are more complex than T-cell and B-cell zones. Different domains are important for different types of immune responses. These domains are in part defined by dynamic, malleable physical structures that guide cell interactions and influence immune outcomes.

Further probing as to how lymph node stromal cells and fibers interact with and determine the character of immune responses should yield fundamental insights into tolerance and immunity. Manipulation of lymph node structure and associated unique cell types and molecules may allow therapeutic interventions in the tolerogenic process.