Beyond tolerance

Regulatory T (T_reg) cells suppress conventional T cell responses, and, in their absence, mice and humans develop autoimmune diseases. Yet, T_reg cells have also been shown to promote protective responses against pathogens. Sebastian Amigorena et al. now report that T_reg cells help focus the CD8⁺ T cell response to nonself antigens by inhibiting low-avidity T cell responses (Science 338, 532–536).

In mice lacking T_reg cells, the researchers found that immunization with a nonself antigen increased the number of antigen-specific CD8⁺ T cells and the frequency of CD8⁺ T cells recognizing the antigen with low avidity. However, these T cells did not promote long-lived memory.

Using two ovalbumin (OVA) peptide variants that are recognized with different affinities by the OT-I T cell receptor, the authors then showed that immunization with dendritic cells (DCs) loaded with the lower-affinity OVA peptide induced little expansion of OT-I T cells in wild-type mice, but marked expansion in T_reg cell–depleted mice. They attributed the expansion of OT-I T cells to increased production by DCs of the chemokines CCL3 and CCL4, which is suppressed by T_reg cells. OT-I T cell recognition of the high-affinity peptide induced high amounts of these cytokines that were not affected by T_reg cell depletion. The researchers further showed that interactions of DCs loaded with the low-affinity peptide and T cells were stabilized in T_reg cell–depleted mice in a CCL3-, CCL4- and/or CCL5-dependent manner.

When the authors infected T_reg cell–depleted mice with Listeria monocytogenes, although the frequency of low-avidity T cells increased during primary infection, these cells were less able to control the bacterial burden upon secondary infection than T cells in T_reg cell–replete mice. These results suggest that T_reg cells are required for the generation of functional T cell memory and a focused, high-avidity CD8⁺ T cell response against pathogens.