Summary NKG2D is a potent activating receptor on NK cells which acts as a molecular sensor for stressed cells expressing NKG2D ligands such as infected or tumor transformed cells. Although NKG2D is expressed on NK cell precursors, its role in NK cell development is still not known. We have generated NKG2D-deficient mice by targeting the Klrk1 locus. Here we provide evidence for an important regulatory role of NKG2D in the development of NK cells. The absence of NKG2D causes faster division of NK cells, perturbation in size of some NK cell subpopulations and their augmented sensitivity to apoptosis. As expected, NKG2D−/− NK cells are less responsive to tumor targets expressing NKG2D ligands. NKG2D−/− mice, however, show an enhanced NK cell-mediated resistance to MCMV infection as a consequence of NK cell dysregulation. Altogether, these findings provide evidence for yet unknown regulatory function of NKG2D in NK cell physiology.

Horizontal transmission of cytomegaloviruses (CMV) occurs via prolonged excretion from mucosal surfaces. We used murine CMV (MCMV) infection to investigate the mechanisms of immune control in secretory organs. CD4 T cells were crucial to cease MCMV replication in the salivary gland (SG) via direct secretion of IFNγ that initiated antiviral signaling on non-hematopoietic cells. In contrast, CD4 T cell helper functions for CD8 T cells or B cells were dispensable. Despite SG-resident MCMV-specific CD8 T cells being able to produce IFNγ, the absence of MHC class I molecules on infected acinar glandular epithelial cells due to viral immune evasion, and the paucity of cross-presenting antigen presenting cells (APCs) prevented their local activation. Thus, local activation of MCMV-specific T cells is confined to the CD4 subset due to exclusive presentation of MCMV-derived antigens by MHC class II molecules on bystander APCs, resulting in IFNγ secretion interfering with viral replication in cells of non-hematopoietic origin.

IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10 −/− mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.

CD4 1 T cells are implied to sustain CD8 1 T-cell responses during persistent infections. As CD4 1 T cells are often themselves antiviral effectors, they might shape CD8 1 T-cell responses via help or via controlling antigen load. We used persistent murine CMV (MCMV) infection to dissect the impact of CD4 1 T cells on virus-specific CD8 1 T cells, distinguishing between increased viral load in the absence of CD4 1 T cells and CD4 1 T-cell-mediated helper mechanisms. Absence of T-helper cells was associated with sustained lytic MCMV replication and led to a slow and gradual reduction of the size and function of the MCMV-specific CD8 1 T-cell pool. However, when virus replication was controlled in the absence of CD4 1 T cells, CD8 1 T-cell function was comparably impaired, but in addition CD8 1 T-cell inflation, a hallmark of CMV infection, was completely abolished. Thus, CD8 1 T-cell inflation during latent CMV infection is strongly dependent on CD4 1 T-cell helper functions, which can partially be compensated by ongoing lytic viral replication in the absence of CD4 1 T cells. IntroductionPersistent viral infections shape their cognate CD8 1 T cells markedly. This is most apparent in chronic infections with continuous productive viral replication such as chronic lymphocytic choriomeningitis virus (LCMV) infection in the mouse, where permanent activation of CD8 1 T cells drives these cells into exhaustion, [1][2][3][4] with the antigen load and/or duration of antigen exposure being major promoters of CD8 1 T-cell exhaustion [5].Low level of antigen persistence as seen during chronic infection with latent, reactivating viruses also shapes antigen-specific CD8 1 T-cell responses, but to a less severe extent than in situations with continuous productive viral replication. Murine CMV (MCMV) is one of the best studied examples of a chronic latent infection. Two types of virus-specific CD8 1 T-cell responses, an inflationary and a non-inflationary, can be distinguished during the course of MCMV infection [6][7][8][9]. CD8 1 T cells of the non-inflationary type resemble CD8 1 T cells that develop during acute resolved infections with respect to their kinetics, function and phenotype [7,[9][10][11][12]. In contrast, inflationary CD8 1 T cells show continued expansion after control of lytic replication, eventually stabilizing at high frequencies [6][7][8][9]. At late stages of infection, these cells are partially exhausted as they lack IL-2 secretion capacity and have reduced TNF-a production potential [7]. MCMV-specific inflationary CD8 1 T cells, in contrast to non-inflationary ones, are dependent on cognate antigen for their maintenance, are unresponsive to homeostatic cytokines [12], and exhibit an effector/effector memory phenotype. In contrast, non-inflationary CD8 1 T cells display a central memory phenotype [12,13].CD4 1 helper T cells were shown to promote priming and/or memory differentiation of CD8 1 T cells in various immunizations and acute infections [10,14]. However, whether and how CD4 1 T cells affect CD8...

The spectrum of tasks which is fulfilled by CD4 T cells in the setting of viral infections is large, ranging from support of CD8 T cells and humoral immunity to exertion of direct antiviral effector functions. While our knowledge about the differentiation pathways, plasticity, and memory of CD4 T cell responses upon acute infections or immunizations has significantly increased during the past years, much less is still known about CD4 T cell differentiation and their beneficial or pathological functions during persistent viral infections. In this review we summarize current knowledge about the differentiation, direct or indirect antiviral effector functions, and the regulation of virus-specific CD4 T cells in the setting of persistent latent or active chronic viral infections with a particular emphasis on herpes virus infections for the former and chronic lymphocytic choriomeningitis virus infection for the latter.