Paxillin Binding to the Cytoplasmic Domain of CD103 Promotes Cell Adhesion and Effector Functions for CD8+ Resident Memory T Cells in Tumors

CD8(+)/CD103(+) tissue-resident memory T cells (T-RM cells) accumulate in several human solid tumors, where they have been associated with a favorable prognosis. However, the role of CD103, the a subunit of the integrin alpha(E)beta(7) (also known as CD103), in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through alpha(E)/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the alpha(E)/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8(+)/CD103(+) lung tumor-infiltrating lymphocytes and CD103(+) tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the alpha(E) chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc-coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers alpha(E)beta(7) integrin outside-in signaling that promotes CD8(+) T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of T-RM cells in the tumor microenvironment. (C) 2017 AACR.