Model of redundancies and complementarities between molecular sensors and cell types for mounting the IFN-I, IFN-γ and cytotoxic cellular immune responses which are necessary for control of MCMV infection.

<p>Based on our own data as well as on many other studies published previously, we propose a model whereby IFN-I, IFN-γ and cytotoxic responses are all necessary for immune defenses against MCMV infection (red lines and text), but access to these functions can be promoted by a number of partly redundant and/or complementary pathways (arrows converging towards a number). IFN-I, IFN-γ and cytotoxic cellular immune responses are critical for control of viral replication, prevention of excessive tissue damage and overall resistance of the host in terms of morbidity and mortality. Several cell types and pathways can lead to IFN-I production. Early after intra-peritoneal injection, MCMV infects stromal cells and other cell types, inducing an IFN-I production by those cells independently of MyD88 and TLRs. In addition, viral particles or material derived from infected cells can be engulfed by cDC and pDC to promote their production of high levels of IFN-I or other cytokines upon triggering of the TLR7/9-to-MyD88 signaling cascade. In our experimental settings, MyD88/TLR9 responses of DC and MyD88-independent responses of infected cells are redundant for the induction of strong IFN-I responses, even though only very low to undetectable levels of IFN-I are produced in the absence of MyD88 responses (❶). In parallel, NK cells and CD8 T cells are able to produce IFN-γ and to specifically recognize and kill MCMV infected cells, via the activation receptor Ly49H or via their TCR, respectively. Cell-mediated immune control of viral replication can thus be performed by both NK and CD8 T cells which can largely compensate one another for this function (❷). However, the antiviral functions of NK and CD8 T cells are not strictly redundant but partly complementary, since, for example, the absence of CD8 T cell responses might increase the risk of selection of viral mutants able to escape NK cell control. MyD88 responses can promote the activation of NK and CD8 T cells via TLR-dependent activation of myeloid cells and/or through cell-intrinsic effects. However, MyD88 responses are not necessary for this function in mice expressing NK cell activation receptors able to directly sense MCMV-infected cells. In these mice, in addition to IFN-I production, MyD88-independent responses from infected cells might provide the other beneficial inflammatory signals necessary for this function (❸). Functional redundancies might also exist between MyD88 responses and NK cell activity for prevention of excessive damage to lymphoid tissues (❹), in order to preserve their micro-anatomical niches supporting the proliferation and survival of CD8 T cells.