Abstract
CD8+ tumor infiltrating T cells (TIL) lack effector-phase functions due to defective proximal TCR-mediated signaling previously shown to result from inactivation of p56lck kinase. We identify a novel interacting partner for p56lck in nonlytic TIL, Protocadherin-18 (‘pcdh18’), and show that pcdh18 is transcribed upon in vitro or in vivo activation of all CD8+ central memory T cells (CD44+CD62LhiCD127+) coincident with conversion into effector memory cells (CD44+CD62LloCD127+). Expression of pcdh18 in primary CD8+ 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+ memory T cells that can function as an inhibitory signaling receptor and restrict the effector phase.
Highlights
CD8+ CTL play an essential role in killing of virus-infected and transformed cells but in unmanipulated hosts fail to control tumor growth
We show that in cells of the hematopoietic lineage pcdh18 is expressed in activated central memory CD8+ T cells (CD44hiCD62LhiCD127hi) coincident with differentiation to the effector memory phenotype: CD8+CD44+CD62LloCD127hi. pcdh18 is expressed in endogenous CD8+ memory cells that accumulate as mice age, or those elicited by prior immunization with various antigens
Identification of a p56lck binding protein in TIL Analysis of p56lck activation status in nonlytic TIL by immuneprecipitation and reciprocal immunoblotting using Ab reactive with the phosphorylated form of the src family kinase inhibitory motif showed that this motif in p56lck was not appreciably phosphorylated upon conjugation in vitro with cognate tumor cells (Fig. 1a)
Summary
CD8+ CTL play an essential role in killing of virus-infected and transformed cells but in unmanipulated hosts fail to control tumor growth. Investigation of animal models and tumor-bearing patients show production of antigen-specific CTL in the periphery but whose effector phase T cell function is suppressed upon entrance to the tumor [2,3], a phenotype postulated to contribute to tumor escape from immune-mediated eradication [4]. This implies the tumor microenvironment induces TIL lytic dysfunction, a conclusion that was substantiated by several experimental approaches [5]. During analysis of TIL p56lck we observed that when nonlytic TIL form conjugates ex vivo with cognate tumor cells, p56lck co-immuneprecipitates with a 120 kD protein, but whose identity and potential role in regulation of TIL function was unknown
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