NK cells negatively regulate CD8 T cells via natural cytotoxicity receptor (NCR) 1 during LCMV infection

Abstract

Besides their function in recognizing cancerous and virally infected cells, natural killer (NK) cells have the potential to shape adaptive immune responses. However, the mechanisms employed by NK cells to negatively regulate virus-specific CD8 T cell responses remain to be fully defined. Using activating receptor natural cytotoxicity receptor (NCR) 1 deficient (NCR1 gfp/gfp ) mice, we found increased numbers of virus-specific CD8 T cells, leading to enhanced virus control during acute LCMV infection. Furthermore, virus-specific CD8 T cells were more activated in the absence of NCR1, resulting in exacerbated immunopathology, documented by weight loss, and superior virus control early during chronic LCMV infection. Transfer experiments of virus-specific CD8 T cells into NCR1 deficient hosts revealed a direct cross talk between NK and CD8 T cells. Studies on the splenic microarchitecture revealed pronounced disorganization of T cells in infected NCR1 gfp/gfp mice, resulting in enhanced immunopathology and disruption of the T cell niche upon chronic LCMV infection. Our data show a novel pathway employed by NK cells to regulate antiviral CD8 T cell responses, namely direct recognition and elimination of activated CD8 T cells via NCR1 early during infection to protect the host from an overshooting T cell response.

NK1.1+ innate lymphoid cells in salivary glands inhibit establishment of tissue‐resident memory CD8+ T cells in mice

“…NKG2D and NKp46 have both been demonstrated to be important for the killing of virus-activated CD8 + T cells by NK cells [3,4,[7][8][9]. The role of these receptors for the regulation of CD8 + T RM cells by SG NK1.1 + cells was tested in P14 chimeric mice lacking NKG2D or NKp46.…”

“…NK cells impair virus-specific T-cell responses indirectly by rapid elimination of antigen-presenting cells [1,2] or directly by cell-mediated lysis of virus-activated T cells [3][4][5][6]. Important molecules in these regulatory pathways are NKG2D and NKp46 as recogni-Correspondence: Prof. Hanspeter Pircher e-mail: pircher@ie-freiburg.mpg.de tion structures and perforin and TRAIL as effector mechanisms [4,5,[7][8][9][10].…”

The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

“…The absence of NCR1 increased the numbers of virus-specific CD8 T cells that leads to enhanced virus control during acute and chronic LCMV infection. However, the increased CD8 T cell responses caused a concomitant pronounced immunopathology in the setting of chronic infection [107]. Furthermore, transfer experiments of virus-specific CD8 T cells into NCR1-deficient mice revealed a direct NK-T cell cross-talk with killing of activated CD8 T cells in an NCR1-dependent manner, which shows a new pathway engaged by NK cells to modulate adaptive T-cell immunity to protect the host from severe immune-mediated damage [107].…”

An Historical Overview: The Discovery of How NK Cells Can Kill Enemies, Recruit Defense Troops, and More

“…It is of note, however, that some viral NCR-Ls can inhibit NCR functions, representing a possible immune evasion strategy (203). It has been very recently demonstrated in mouse that NK cells may play a regulatory role during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection through the NKp46-mediated killing of LCMV-specific CD8 T cells (204).…”