Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Abstract

The immunoreceptor NKG2D stimulates activation of cytotoxic lymphocytes upon engagement with MHC class I-related NKG2D ligands of which at least some are expressed inducibly upon exposure to carcinogens, cell stress, or viruses. In this study, we investigated consequences of a persistent NKG2D ligand expression in vivo by using transgenic mice expressing MHC class I chain-related protein A (MICA) under control of the H2-Kb promoter. Although MICA functions as a potent activating ligand of mouse NKG2D, H2-Kb-MICA mice appear healthy without aberrations in lymphocyte subsets. However, NKG2D-mediated cytotoxicity of H2-Kb-MICA NK cells is severely impaired in vitro and in vivo. This deficiency concurs with a pronounced down-regulation of surface NKG2D that is also seen on activated CD8 T cells. As a consequence, H2-Kb-MICA mice fail to reject MICA-expressing tumors and to mount normal CD8 T cell responses upon Listeria infection emphasizing the importance of NKG2D in immunity against tumors and intracellular infectious agents.

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

“…Down-modulation of other receptors by Tg expression of their corresponding ligand has been described before, e.g. for NKG2D and Ly49H [35,36].Constitutive CD70 expression not only compromised CD27 expression, but CD70-Tg mice suffered from a general reduction in NK cell numbers as well. Indeed, a sharp decrease of absolute NK cell numbers was established in CD70-Tg BM, spleen and liver.…”

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

“…Although IL-15 may have directly affected CD8 + T cellmediated effector functions, our results raise the hypothesis that during experimental TB the expression of protective effector mechanisms through antigenspecific CD8 + T cells depends to some extent on IL-15-induced NKG2D. However, only analysis of mice defective in NKG2D-dependent effector mechanisms [53,54] will disclose the significance of NKG2D engagement on CD8 + T cell-mediated protection against Mtb infection in vivo. …”

“…NKG2D signaling favors the development of effector CD8 + T cells [51] and augments cytotoxic and proliferative responses of CD8 + T cells on antigen encounter [32,52], thus qualifying NKG2D as an important T cell costimulatory molecule during infection. Indeed, Listeria monocytogenes infection of mice defective in NKG2D-mediated cytotoxicity revealed a significant role of NKG2D engagement for NK and CD8 + T cell-mediated effector mechanisms and protection during infection [53].After infection with Mtb, we noted an up-regulation of NKG2D ligands on lung macrophages from wild-type mice and speculated that the expression of NKG2D on CD8 + T cells might be involved in mediating CD8 + T cell-mediated effector mechanisms. Indeed, inhibition of NKG2D receptor engagement abrogated effector mechanisms of antigen-specific CD8 + T cells purified from Mtb-infected wild-type mice.…”

“…NKG2D signaling favors the development of effector CD8 + T cells [51] and augments cytotoxic and proliferative responses of CD8 + T cells on antigen encounter [32,52], thus qualifying NKG2D as an important T cell costimulatory molecule during infection. Indeed, Listeria monocytogenes infection of mice defective in NKG2D-mediated cytotoxicity revealed a significant role of NKG2D engagement for NK and CD8 + T cell-mediated effector mechanisms and protection during infection [53].…”

Requirements for control of B‐cell lymphoma by NK cells

“…4D). In mice expressing transgenic human NKG2D-L or harboring NKG2D-Lexpressing tumor cells, NKG2D down-regulation was also observed [40][41][42].…”