Weak vaccinia virus-induced NK cell regulation of CD4 T cells is associated with reduced NK cell differentiation and cytolytic activity

• Published in: Virology (New York, N.Y.) N.Y.), 2018-06, Vol.519, p.131-144
• Main Authors: Hatfield, Steven D., Daniels, Keith A., O’Donnell, Carey L., Waggoner, Stephen N., Welsh, Raymond M.
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - immunology; CD4 T cells; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Cytotoxicity, Immunologic; Granzymes - genetics; Immunity, Humoral; Interferon; Interferon Regulatory Factors - genetics; IRF4; Killer Cells, Natural - immunology; Killer Cells, Natural - physiology; LCMV; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lymphocyte Activation; Lymphocytic Choriomeningitis; Mice; Mice, Inbred C57BL; NK Cell Lectin-Like Receptor Subfamily C - genetics; NK cells; NKG2A; Perforin - genetics; Vaccinia - immunology; Vaccinia virus; Vaccinia virus - genetics; Vaccinia virus - immunology
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2018.04.012

Natural killer (NK) cells control antiviral adaptive immune responses in mice during some virus infections, but the universality of this phenomenon remains unknown. Lymphocytic choriomeningitis virus (LCMV) infection of mice triggered potent cytotoxic activity of NK cells (NKLCMV) against activated CD4 T cells, tumor cells, and allogeneic lymphocytes. In contrast, NK cells activated by vaccinia virus (VACV) infection (NKVACV) exhibited weaker cytolytic activity against each of these target cells. Relative to NKLCMV cells, NKVACV cells exhibited a more immature (CD11b-CD27+) phenotype, and lower expression levels of the activation marker CD69, cytotoxic effector molecules (perforin, granzyme B), and the transcription factor IRF4. NKVACV cells expressed higher levels of the inhibitory molecule NKG2A than NKLCMV cells. Consistent with this apparent lethargy, NKVACV cells only weakly constrained VACV-specific CD4 T-cell responses. This suggests that NK cell regulation of adaptive immunity, while universal, may be limited with viruses that poorly activate NK cells. •NKVACV cells are atypically poor killers of CD4 T cells early in infection.•NKVACV cells are less cytotoxic and mature than CD4 T cell-killing NKLCMV cells.•The inhibitory receptor NKG2A is enriched in NKVACV cells.•Poor cytotoxicity of NKVACV cells corresponds to low IFN-I and IRF-4 expression.•Nevertheless, NKVACV cells still partially reduce the CD4 response by day 14 of infection.