CD4 and viral infectious disease: During acute viral infections, systemic infections, and in the tumor microenvironment NK cells can dysregulate CD4+ and CD8+ T cell responses promoting pathogen and tumor persistence and immune exhaustion (Perona-Wright et al., 2009; Lang et al., 2012; Waggoner et al., 2012, 2014; Cook and Whitmire, 2013; Crouse et al., 2014; Schuster et al., 2014; Cook et al., 2015; Crome et al., 2017).