Peripheral positioning

Credit: S.Bradbrook/NPG

FOXP3⁺ regulatory T cells (T_Reg cells) prevent autoimmunity by controlling self-reactive T cells in the periphery that have escaped negative selection. But little is known about where T_Reg cells are positioned in lymph nodes and how exactly they maintain immune homeostasis. This Nature paper, from the Germain laboratory, provides a new view on how T_Reg cells suppress self-reactive T cells to mediate immune homeostasis in peripheral tissues.

Using a recently described method of multiplex, quantitative imaging, termed histocytometry, Liu et al. observed that, in contrast to other FOXP3⁺ T_Reg cells that were distributed through the lymph node, FOXP3⁺ T_Reg cells expressing phosphorylated signal transducer and activator of transcription 5 (pSTAT5) primarily localized in a few discrete aggregates in the outer paracortical T cell region of lymph nodes of healthy mice. pSTAT5 is induced by interleukin-2 (IL-2), which is essential for maintaining T_Reg cell function, suggesting that these cells were actively responding to an IL-2 signal. Indeed, most of the pSTAT5⁺ T_Reg cells in these clusters, particularly those towards the centre of the cluster, expressed high levels of the suppressive molecules CD73 and cytotoxic T lymphocyte antigen 4 (CTLA4).

These T_Reg cell clusters preferentially contained CD11b⁺MHC class II^hi migratory dendritic cells (DCs), and some of them contained individual IL-2-producing CD4⁺ T cells, although the frequency of IL-2-producing cells in the lymph nodes was extremely low. So, what is driving IL-2 production by these T cells? Based on the observation that cluster formation was unaffected in germ-free mice, the authors concluded that these CD4⁺ T cells were activated by self-antigens, possibly presented by the migratory DCs. These data suggest that even in the presence of T_Reg cells, a small fraction of T cells can be sufficiently activated by self-antigen in the steady state to become IL-2-producing 'proto-effector' T cells.

In addition to IL-2, TCR signals are necessary for T_Reg cell function in the periphery. Conditional deletion of TCRα in T_Reg cells resulted in a disrupted spatial distribution of T_Reg cells, with fewer T_Reg cells forming discrete clusters. Furthermore, CD73 and CTLA4 expression levels were reduced, particularly at the centre of the clusters.

Finally, blocking IL-2 function in the steady state resulted in an increase in the frequency and total number of IL-2-producing CD4⁺ T cells in the spleen and lymph nodes. Further studies confirmed that T_Reg cell-sensing of IL-2 produced by proto-effector T cells is essential for T_Reg cell-mediated suppression of self-antigen-induced T cell activation and maintenance of self-tolerance.

So, this study suggests that TCR signals help T_Reg cells to localize in clusters with self-reactive T cells in the steady state where they sense IL-2 to prevent autoimmune responses.