Elimination of only one type of inhibitory receptor with even a weak inhibitory potential may therefore not be sufficient to detectably alter their functional activity. It

is also possible that the loss of KLRG1 in NK or T cells is compensated by altered expression of other cell surface recognition structures. The observed increased reactivity of NK cells from KLRG1 KO mice toward E-cadherin-transfected target cells was unexpected. Besides KLRG1, there is only one additional receptor, αEβ7 (CD103), known to be expressed on lymphocytes that can bind E-cadherin 35. However, the NK cells used in our experiments did not express CD103 (data not shown). In addition to its adhesive role, E-cadherin is also involved in the Wnt signaling pathway by sequestering β-catenin and is also known INCB024360 to inhibit the ligand activation of receptor tyrosine kinases 36. Thus, it is possible that ectopic expression of E-cadherin in K562 cells alters click here the expression of other yet undefined cell surface molecules that may play a role in NK-cell recognition. KLRG1 expression has been associated with distinct stages during NK and T-cell differentiation and differences between KLRG1+ and KLRG1− lymphocytes subsets have been demonstrated in several instances. This includes the decreased ability of MCMV-activated KLRG1+ NK cells to produce IFN-γ 21, the low level of KLRG1 expression by non-responsive NK cells lacking self-MHC-specific

inhibitory receptors 20, 37, the impaired capacity of KLRG1+ effector/memory T cells to proliferate 7, 11, 13, 14, 29, the paucity of KLRG1+ effector/memory cells to produce IL-2 and inability Carnitine palmitoyltransferase II of KLRG1+ effector cells to give raise to long-lived memory T cells 15, 16. Importantly, the experiments performed here revealed

that KLRG1 serves as marker for these lymphocyte differentiation stages and their functional characteristics but it does not play a deterministic role. Of note, treatment of B6 mice with anti-KLRG1 mAb did also not affect induction of LCMV-specific CD8+ T cells determined by MHC class I tetramer staining and did also not influence the extent of CD62L- and CD127-downregulation in these cells during the acute phase of the infection (data not shown). Even though our study did not reveal alterations of immune functions in the absence of KLRG1, we certainly cannot exclude the possibility that KLRG1 regulates T-cell or NK-cell functions that we have not investigated in this first characterization of these mice. We have recently observed that KLRG1-E-cadherin binding can also strengthen the interaction between cells 26. Thus, the effect of KLRG1 deficiency on lymphocyte adhesion in epithelial tissues expressing E-cadherin such as lung, intestine or skin will have to be tested. In addition, autoimmune models in which slightly activated lymphocytes persist in such tissues could now be used together with the KLRG1-deficient mice generated here.