Viral, bacterial or parasite infections

strongly induce KLRG1 expression in NK cells and T cells and most T cells with effector or effector-memory phenotypes are KLRG1+8–11. T cells expressing KLRG1 have normal effector functions but the proliferative capacity of these cells is impaired 7, 11–14. In addition, KLRG1 was shown to serve as a marker for short-lived effector CD8+ T cells during viral infection 15, 16. Within the NK-cell population, KLRG1 is predominantly found in the most mature CD11b+CD27− NK-cell subset in mice 17–19 and in CD56dim NK cells in humans 7. Of interest, NK cells from MHC-class-I-deficient mice express lower levels of KLRG1 20. Moreover, KLRG1 expression by NK cells after murine cytomegalovirus (MCMV) FDA approval PARP inhibitor infection has been demonstrated to inversely correlate with the ability to produce IFN-γ 21. Thus, similar to T cells, KLRG1 is also a marker for NK cells that are approaching the end PS-341 mouse of their differentiation stage. Members of the classical cadherin family have been identified

as ligands for both human and mouse KLRG1 22–25. In addition, inhibition of T and NK-cell function by interaction of KLRG1 with E-cadherin has been demonstrated in some but not all experimental settings 22–24, 26. These findings suggested a role for KLRG1 in dampening KLRG1+ lymphocytes in tissues expressing cadherins in order to prevent immunopathology 27. The crystal structure of KLRG1 in complex with E-cadherin has recently been solved 28. It shows that KLRG1 binds to a highly conserved site on cadherins that overlaps with the site involved in homophilic trans interaction but is distinct from the αEβ7 (CD103) binding site. An exceptionally weak affinity

of KLRG1 to cadherins has further been noted substantiating the notion that KLRG1–cadherin interaction occurs through multivalent binding and involves the formation of multimeric receptor/ligand complexes 26. Despite KLRG1 being widely Ribonucleotide reductase used as a lymphocyte differentiation marker, and the substantial progress made in structural and functional characterization of KLRG1, the role of KLRG1 in vivo is still poorly defined. To address this issue, we generated KLRG1-deficient mice by homologous recombination. The characterization of these mice indicates that KLRG1 is dispensable for normal CD8+ T-cell differentiation and memory cell formation after viral infections. In addition, KLRG1 deficiency did not affect development and function of NK cells in the various assays used in this study. KLRG1-deficient mice were generated by homologous recombination using a targeting construct that carries a lacZ reporter gene and a neo cassette inserted into the third exon of the mouse Klrg1 gene (Fig. 1A). This exon encodes the neck region and the proximal half of the C-type lectin domain of KLRG1 2. A homologous recombinant HM1 ES cell clone (M31) was injected into B6 blastocysts and resulting 129/B6 chimeric mice were crossed with B6 mice to attain germ line transmission.