NK cells controlling virus-specific T cells: Rheostats for acute vs. persistent infections

Abstract

Viral infections characteristically induce a cytokine-driven activated natural killer (NK) cell response that precedes an antigen-driven T cell response. These NK cells can restrain some but not all viral infections by attacking virus-infected cells and can thereby provide time for an effective T cell response to mobilize. Recent studies have revealed an additional immunoregulatory role for the NK cells, where they inhibit the size and functionality of the T cell response, regardless of whether the viruses are themselves sensitive to NK cells. This subsequent change in T cell dynamics can alter patterns of immunopathology and persistence and implicates NK cells as rheostat-like regulators of persistent infections.

Figure 1. Innate and adaptive host response to infection

This figure portrays the timing of the peaks in innate cytokines (type 1 IFN, etc), NK cell cytolytic activity (not cell number), and T cell number and activity during an acute viral infection, based on (Welsh, 1978).

Figure 2. Pathogenesis of LCMV infection at different viral doses in normal or NK cell-depleted mice

The red area is the zone of severe immune pathology, where there are sufficient amounts of virus and T cells to cause tissue damage. At a higher dose of virus the T cells exhaust, and at a lower dose the virus is cleared. NK cell depletion results in a stronger T cell response, which changes the dose at which immune pathology occurs (Waggoner et al., 2012).

Figure 3. In vivo cytotoxicity assay

Splenocytes from NK cell-depleted, virus-infected Ly5.1+ mice are labeled with CFSE and transferred into infected or uninfected recipients deleted or not of NK cells. After 5 hours donor target cells are gated for CD4 or CD8, and the numbers of cells expressing activation antigens (e.g. CD43 and CD44) are quantified (Waggoner et al., 2012).

Figure 4. NK cells regulate the T cell response by acting on CD4 T cells

This diagrams how NK cells can regulate the overall T cell response by attacking activated helper CD4 T cells. This allows for excess viral antigen that can exhaust both CD4 and CD8 T cells.