CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help

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Abstract
Successful defence against intracellular pathogens requires neutralizing antibodies and cytotoxic CD8+ T lymphocyte (CTL) responses, both largely dependent on the activity of CD4+ T helper cells. Nakanishi et al. report a previously unrecognized aspect of CD4 help in the CTL response: CD4+ T cells are required for the recruitment of CD8+ T cells to mucosal sites of viral infection. The CD4+ T-cell help requires the secretion of interferon-γ and the induction of local chemokine secretion. CD4+ T helper cells provide critical signals for the generation of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo as well as promoting protective CD8+ memory T-cell development. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here, fully helped effector CTLs are shown to rely on CD4+ T cells to provide the necessary cue for entry into infected tissue. CD4+ T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8+ memory T-cell development1. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4+ T cells to provide the necessary cue. CD4+ T helper cells control the migration of CTL indirectly through the secretion of IFN-γ and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells.