NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

Abstract

Inoculation with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice results in an acute encephalitis associated with an immune-mediated demyelinating disease. During acute disease, infiltrating CD8 ؉ T cells secrete gamma interferon (IFN-␥) that controls replication in oligodendrocytes, while infected astrocytes and microglia are susceptible to perforin-mediated lysis. The present study was undertaken to reveal the functional contributions of the activating NKG2D receptor in host defense and disease following JHMV infection. NKG2D ligands RAE-1, MULT1, and H60 were expressed within the CNS following JHMV infection. The immunophenotyping of infiltrating cells revealed that NKG2D was expressed on ϳ90% of infiltrating CD8 ؉ T cells during acute and chronic disease. Blocking NKG2D following JHMV infection resulted in increased mortality that correlated with increased viral titers within the CNS. Anti-NKG2D treatment did not alter T-cell infiltration into the CNS or the generation of virus-specific CD8 ؉ T cells, and the expression of IFN-␥ was not affected. However, cytotoxic T-lymphocyte (CTL) activity was dependent on NKG2D expression, because anti-NKG2D treatment resulted in a dramatic reduction in lytic activity by virus-specific CD8 ؉ T cells. Blocking NKG2D during chronic disease did not affect either T-cell or macrophage infiltration or the severity of demyelination, indicating that NKG2D does not contribute to virus-induced demyelination. These findings demonstrate a functional role for NKG2D in host defense during acute viral encephalitis by selectively enhancing CTL activity by infiltrating virus-specific CD8 ؉ T cells.Viral infection of the central nervous system (CNS) presents unique challenges to the immune system with regard to controlling and eliminating the invading pathogen. These obstacles include the presence of a blood-brain barrier that provides a physical and physiological barrier that is difficult for cells and molecules to cross, the absence of classic lymphatic drainage that may impair the generation of an adaptive immune response, and the relative absence of major histocompatibility complex (MHC) class I or II expression on resident cells (3,26,39,73). In addition, the CNS is composed of a variety of highly specialized cells, many of which have limited renewal capacity, that represent potential targets of infection by numerous different viruses (34, 81). Therefore, a significant hurdle encountered by infiltrating antigen-specific lymphocytes is the elimination of virus from infected cells while limiting the damage that may have long-term detrimental consequences to the host. Critical to this is the cellular tropism of the virus, as this is important in dictating the effector response by infiltrating lymphocytes. For example, neuronotropic viruses often are eliminated by noncytolytic mechanisms via cytokine-mediated control and/or neutralizing antibodies, whereas the infection of other cell populations can evoke cytolytic mechanisms for c...

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

“…Like NKG2D C NK and NK T cells, NKG2D C T cells eliminate bacterially infected NKG2D ligand C cells 22 as well as the JHM strain of mouse hepatitis virus in the central nervous system in mice with acute disease. 23 Unlike with NKG2D C NK and NK T cells, however, NKG2D expression rescues CD8 C T-cell memory in the absence of CD4 C T-cell assistance. 21 In a colon cancer model, NKG2D activation on the surface of intraepithelial lymphocytes induced Fas ligand production and cytotoxicity independent of TCR signaling, suggesting a particular characteristic of NKG2D on CD8 C intraepithelial lymphocytes.…”

“…However, the biology of NKG2D receptor was primarily determined via investigation of NK cells. Increasing evidence demonstrates that NKG2D C T cells enhance memory features, 21 defend against tumor cells and pathogens, 6,22,23 and balance the effective and regulatory characteristics of T cells, 24 suggesting a substantial role for NKG2D in cross-talk between innate and adaptive immune responses. Like NKG2D C NK and NK T cells, NKG2D C T cells eliminate bacterially infected NKG2D ligand C cells 22 as well as the JHM strain of mouse hepatitis virus in the central nervous system in mice with acute disease.…”

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

“…Moreover, we demonstrate that the reduction in NKG2D expression is sufficient to inhibit NKG2D-dependent costimulation of memory CD8 T cells. This could impact the efficiency of memory CD8 T cell responses given that a contribution of NKG2D expression in CD8 T cell-mediated protection has been documented in several pathological contexts such as bacterial or viral infections (12,13,40). A diversity of signals can inhibit NKG2D expression such as CD4 T cell-derived soluble NKG2D ligands (9) or cytokines: indeed, a number of gc cytokines have been shown to regulate NKG2D expression in several contexts, but these cytokines come in two flavors, inhibitors or inducers.…”

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

“…This process consists in inducing target cell death through cytotoxic effector cells. Natural killer (NK) cells and CD8 + T cells are two of the main cell populations considered as cytotoxic cells, because their most important activity is to remove abnormal or infected cells to prevent the development of malignancies, and to eliminate intracellular pathogens (1)(2)(3)(4).…”

“…NKG2A, B, C, E, or F receptors are expressed on NK cells, CD8 + TCR  and  lymphocytes, CD4 + T cell subsets, and NKT cells (1,10,(22)(23)(24)(25), all of which recognize HLA-E (17,21,(26)(27)(28) complexed to an MHC class I leader sequence (29). In this fashion, they monitor the expression of MHC-I molecules on target cells.…”