title: Lack of functional selectin ligand interactions compromises long term tumor protection by CD8+ T cells.
abstract: Central memory CD8(+) T cells expressing the adhesion molecule CD62L (L-selectin) are potent mediators of anti-cancer immunity due to their ability to proliferate extensively upon antigen re-stimulation. The interaction of selectin with its ligands mediates leukocyte rolling along high endothelial venules. Mice deficient in α(1,3) Fucosyltransferase IV and VII (FtDKO) lack functional L, P and E selectin ligands. Thus, we addressed whether the lack of selectin ligand interactions alters tumor protection by CD8(+) T cells in FtDKO mice. Listeria monocytogenes-OVA (LM-OVA) infection evoked potent OVA-specific CD8(+) T cells that proliferated and contracted at similar kinetics and phenotype in FtDKO and wild-type mice. Additionally, OVA-specific CD8(+) T cells in both mouse strains exhibited similar phenotypic differentiation, in vivo cytolytic activity and IFN-γ expression. However, FtDKO mice succumbed to B16-OVA tumors significantly earlier than wild-type mice. In contrast, FtDKO mice evoked strong recall memory CD8(+) T cell responses and protection to systemic LM-OVA re-challenge. The diminished tumor protection in FtDKO mice was not related to defective antigen presentation by dendritic cells or reduced proliferation of antigen-specific CD8(+) T cells. However, WT or FtDKO OVA-specific CD8(+) T cells showed significantly reduced ability to traffic to lymph nodes upon adoptive transfer into naïve FtDKO recipients. Furthermore, FtDKO OVA-specific CD8(+) T cells displayed poor ability to infiltrate tumors growing in WT mice. These results reveal that selectin ligand expression on host endothelium as well CD8(+) T cells may be important for their efficient and continued extravasation into peripheral tumors.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Felicity C
authors.initials: FC
authors.lastname: Stark
authors.forename: Komal
authors.initials: K
authors.lastname: Gurnani
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnan
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005647:Fucosyltransferases; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D010047:Ovalbumin; D019087:Selectins / Q000276:immunology*
chemical_list: D008024:Ligands; D019087:Selectins; D010047:Ovalbumin; D005647:Fucosyltransferases