Regulatory T (Treg) cells suppress conventional T cell responses, and, in their absence, mice and humans develop autoimmune diseases. Yet, Treg cells have also been shown to promote protective responses against pathogens. Sebastian Amigorena et al. now report that Treg 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 Treg 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 Treg 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 Treg cells. OT-I T cell recognition of the high-affinity peptide induced high amounts of these cytokines that were not affected by Treg cell depletion. The researchers further showed that interactions of DCs loaded with the low-affinity peptide and T cells were stabilized in Treg cell–depleted mice in a CCL3-, CCL4- and/or CCL5-dependent manner.
When the authors infected Treg 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 Treg cell–replete mice. These results suggest that Treg cells are required for the generation of functional T cell memory and a focused, high-avidity CD8+ T cell response against pathogens.
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Farrell, A. Beyond tolerance. Nat Med 18, 1752 (2012). https://doi.org/10.1038/nm.3035