Protocadherin-18 Is a Novel Differentiation Marker and an Inhibitory Signaling Receptor for CD8.sup.+ Effector Memory T Cells

CD8.sup.+ tumor infiltrating T cells (TIL) lack effector-phase functions due to defective proximal TCR-mediated signaling previously shown to result from inactivation of p56.sup.lck kinase. We identify a novel interacting partner for p56.sup.lck in nonlytic TIL, Protocadherin-18 ('pcdh18'), and show that pcdh18 is transcribed upon in vitro or in vivo activation of all CD8.sup.+ central memory T cells (CD44.sup.+ CD62L.sup.hi CD127.sup.+) coincident with conversion into effector memory cells (CD44.sup.+ CD62L.sup.lo CD127.sup.+). Expression of pcdh18 in primary CD8.sup.+ effector cells induces the phenotype of nonlytic TIL: defective proximal TCR signaling, cytokine secretion, and cytolysis, and enhanced AICD. pcdh18 contains a motif (centered at Y842) shared with src kinases (QGQYQP) that is required for the inhibitory phenotype. Thus, pcdh18 is a novel activation marker of CD8.sup.+ memory T cells that can function as an inhibitory signaling receptor and restrict the effector phase.