Cutting Edge: NKG2D Receptors Induced by IL-15 Costimulate CD28-Negative Effector CTL in the Tissue Microenvironment

Abstract

Unlike primary T cells in lymph nodes, effector CD8+ CTL in tissues do not express the costimulatory receptor CD28. We report that NKG2D, the receptor for stress-induced MICA and MICB molecules expressed in the intestine, serves as a potent costimulatory receptor for CTL freshly isolated from the human intestinal epithelium. Expression and function of NKG2D are selectively up-regulated by the cytokine IL-15, which is released by the inflamed intestinal epithelium. These findings identify a novel CTL costimulatory pathway regulated by IL-15 and suggest that tissues can fine-tune the activation of effector T cells based on the presence or absence of stress and inflammation. Uncontrolled secretion of IL-15 could lead to excessive induction of NKG2D and thus contribute to the development of autoimmune disease by facilitating the activation of autoreactive T cells.

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

“…Moreover, our results suggest a novel link between the expression of the C-type lectinlike receptor NKG2D, shown to be dependent on IL-15 [29,30], and CD8 + T cell effector functions during experimental TB. 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.…”

“…NKG2D signalling is mediated by the adaptor molecule DAP10 [28] through a YXXM motif similar to that of CD28, a costimulator of naive T cells. Importantly, the expression of NKG2D and DAP10 was described to be dependent on IL-15 [29,30]. Because infection induces the expression of MHC class I-like ligands for NKG2D on macrophages such as Rae-1 [31-33], we first analysed whether infection with Mtb induces the expression of the NKG2D ligand Rae-1 on pulmonary macrophages (Fig.…”

“…NKG2D signalling is mediated by the adaptor molecule DAP10 [28] through a YXXM motif similar to that of CD28, a costimulator of naive T cells. Importantly, the expression of NKG2D and DAP10 was described to be dependent on IL-15 [29,30].…”

“…Indeed, inhibition of NKG2D receptor engagement abrogated effector mechanisms of antigen-specific CD8 + T cells purified from Mtb-infected wild-type mice. However, we cannot exclude the possibility that in addition to NKG2D expression on CD8 + T cells its presence on NK cells may have had an impact on protective anti-mycobacterial effector mechanisms in vivo.IL-15 has been described to induce NKG2D expression on CD8 + T cells [29] and to suppress its downregulation in activated CD8 + T cells [51]. In support of these data, the present report reveals that the expression of NKG2D in activated CD8 + T cells is dependent on IL-15, indicating that a failure to up-regulate this costimulatory receptor complex may have contributed to the reduced antigen-specific production of IFN-c and cytotoxicity by CD8 + T cells in the absence of IL-15.…”

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

“…8,9 In addition, IL-15 upregulates the expression of NKG2D on NK and T cells, even in the presence of soluble NKG2DL. 10 IL-15 and NKG2D signals cross-regulate each other and work together to influence the development and function of NK cells. 11,12 Furthermore, IL-15 augments NKG2DL-mediated antitumor responses by promoting the accumulation of NK, NK1.1 and T cells in tumors.…”