T_Reg cells separate the weak from the strong

Credit: NPG

Regulatory T (T_Reg) cells are known for their role in peripheral tolerance and are essential for preventing autoimmunity. But do they play a part during active immune responses to foreign antigens? In a new study, Amigorena and colleagues demonstrate that T_Reg cells enhance the avidity of CD8⁺ T cell responses to foreign antigens and thereby improve T cell memory.

this mechanism could ... explain how T_Reg cells seemingly distinguish between autoimmune and foreign-antigen-specific responses

In initial experiments in mice, the authors showed that T_Reg cell depletion during the priming stage of a CD8⁺ T cell response to an injected foreign antigen markedly increased the numbers of antigen-specific CD8⁺ T cells in the spleen. Interestingly, however, the vast majority of these T cells recognized the antigen with only low avidity, and thus the overall avidity of the response was reduced in the absence of T_Reg cells. By contrast, the depletion of T_Reg cells at later time points affected only the proportion of antigen-specific T cells and not their avidity. This implies that T_Reg cells might function during the priming of CD8⁺ T cells to suppress low-avidity responses to foreign antigens.

But how do T_Reg cells exert these effects? Intravital imaging of naive T cell receptor (TCR)-transgenic CD8⁺ T cells interacting with antigen-loaded dendritic cells (DCs) in lymph nodes showed that the long-lasting interactions induced by a high-affinity antigen were unaltered by T_Reg cell depletion. By contrast, the shorter duration T cell–DC contacts induced by a low-affinity antigen were extended in the absence of T_Reg cells. This effect could be reversed by the addition of blocking antibodies specific for CC-chemokine ligand 3 (CCL3), CCL4 and CCL5, suggesting that T_Reg cells inhibit the production of chemokines that stabilize low-affinity T cell–DC interactions.

These findings were corroborated in an in vivo infection model using ovalbumin-expressing Listeria monocytogenes. Again, a lack of T_Reg cells at the priming stage decreased the avidity of the ovalbumin-specific CD8⁺ T cell response. This was associated with a reduction in T cell interferon-γ production and a rise in the production of CCL2, CCL3 and CCL4 in the spleen. Although no impact on the clearance of the primary infection was observed in this model, the depletion of T_Reg cells prior to the primary infection resulted in higher bacterial burdens during a secondary infection. In addition, there were corresponding decreases in the number and relative affinities of ovalbumin-specific CD8⁺ T cells during the secondary response. This suggests that the presence of T_Reg cells during naive T cell priming promotes the subsequent generation of functionally effective high-avidity memory CD8⁺ T cell responses.

So, this study reveals an intriguing new role for T_Reg cells in the suppression of low-avidity CD8⁺ T cell responses to foreign antigens. As most autoreactive T cells in the periphery have only low affinities for self antigens, the authors propose that this mechanism could also underlie the T_Reg cell-mediated suppression of these cells and may thus explain how T_Reg cells seemingly distinguish between autoimmune and foreign-antigen-specific responses.