Dynamic interaction of PSGL-1 with the T cell receptor regulates the extent of T cell activation

Abstract

Abstract We previously identified PSGL-1 (P-selectin glycoprotein-1) as a T cell-intrinsic, cell surface checkpoint inhibitor during chronic viral infection. In this model, we found that cross-linking PSGL-1 with antibody reduced signaling through the T cell receptor (TCR) in exhausted T cells and further upregulated PD-1 expression. However, the function of PSGL-1 in the early activation of naïve T cells has not been fully investigated. We found that, crosslinking PSGL-1 on naïve T cells augments TCR signaling, including enhanced Erk and Akt phosphorylation and Nur77 expression. In addition, T cells expressed more activation markers, including PD-1, proliferated to a greater extent, and secreted more cytokines when PSGL-1 was crosslinked compared to TCR stimulation alone, indicating a role as a costimulatory molecule. Strikingly, we have discovered that PSGL-1 co-localizes with the TCR upon stimulation. CD3 and PSGL-1 can be found in the same micro vesicles following anti-CD3 crosslinking, indicating a close connection between PSGL-1 and the TCR. However, the effects of PSGL-1 ligation are similar to what is seen in T cells that lack PSGL-1 expression, except with respect to PD-1 expression. We propose that decreased induction of PD-1 with PSGL-1 deficiency supports greater effector T cell responses. Further studies will address the function of PSGL-1 in cytoskeletal rearrangement and the formation of the immune synapse. Altogether, these data indicate that the extent of T cell activation is regulated by an association of PSGL-1 with the TCR.