Imaging tolerance

The behavior of naive T cells in the lymph nodes does not betray their fate, according to new footage from live lymph nodes. On page 1815, Zinselmeyer and colleagues show that the movements of CD4⁺ T cells destined for tolerance differ only subtly from those destined for priming, suggesting that tolerance cannot be explained by an overt failure of the T cells to stop so that they can receive a priming signal.Intravital imaging technology has revealed that naive T cells dart rapidly around lymph nodes in search of their antigen, briefly contacting antigen presenting cells (APCs) as they go. An encounter with a cognate antigen delivers a stop signal that triggers stable T cell–APC interactions. When this encounter breaks up, the T cells resume their frenetic activity.

Interactions between T cells and APCs may, under certain conditions, lead to T cell tolerance instead of priming. Disruption of the choreographed T cell behavior in the lymph node is one possible explanation for the distinct functional outcomes. This idea was supported by a recent study showing that CD8⁺ T cells failed to form stable interactions with dendritic cells under tolerizing conditions, suggesting that the lack of a prolonged signal from the APC may lead to T cell tolerance.

Zinselmeyer et al. now show, however, that CD4⁺ T cells in lymph nodes of mice fed antigen with or without adjuvant (to induce priming or tolerance) behaved similarly. Under both conditions, naive T cells formed stable clusters with APCs, although the clusters were smaller and shorter-lived under tolerizing conditions. The authors suggest that subtle differences in T cell clustering, and perhaps the quality of the signal delivered by the APC—rather than the complete presence or absence of a stable interaction—may decide the fate of the T cell.

Shakhar and colleagues, reporting in Nature Immunology (doi:10.1038/ni1210), also found only subtle differences in CD4⁺ T cell behavior in priming or tolerizing conditions. They found that stable T–DC interactions were predictive of T cell activation and proliferation, but not tolerance induction. They speculate that late, dynamic T cell-APC interactions that occur after the T cells resume their motion may deliver the fate-deciding signal.