UC San Diego

Integrins are essential for all the T cell functions. Integrins can enable T cells to migrate in and out of lymph nodes and other tissues and mediate cell-to-cell interactions. Integrin activation also plays a critical role in maintaining regulatory T (Treg) cell function. Rap1 is a small GTPase playing an essential role in recruitment and tethering of talin1 to the integrin cytoplasmic domain, which results in integrin activation. Rap1 can bind to talin1 directly. Previous work showed that the Rap1–talin1 F0 domain interaction has a minimum effect on platelet activation. Our lab recently identified an additional Rap1 binding site in the talin1 F1 domain, which is critical for integrin activation in platelets. However, the relative roles of these two binding sites for integrin activation on lymphocytes are still obscure. Here, by testing talin1 mice bearing point mutations, which block Rap1 binding without affecting talin1 expression, in talin1 F0 and F1 domains (R35E, R118E), we found that the binding between talin1 and Rap1 plays a key role in T cell adhesion and migration. The loss of direct interaction between talin1and Rap1 also leads to defects in the suppressive function of Treg cells specifically. Taken together, talin1 is a direct effector of Rap1 GTPase that mediates integrin activation in both CD4+ T cells and Treg cells.