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

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Abstract

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.

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Figure 1: CD4 help is required for CTL migration into the vaginal mucosa after HSV-2 infection.
Figure 2: CD4 T cell-secreted IFN-γ mediates CTL entry into infected vaginal tissue.
Figure 3: CTL recruitment to the infected tissue depends on CXCR3.
Figure 4: Secretion of CTL-recruiting chemokines in the infected tissue depends on CD4 T-cell help.

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Acknowledgements

We thank F. R. Carbone and W. R. Heath for the gBT-I transgenic mouse, A. Rudensky for the foxp3 knock-in mouse, R. Medzhitov and J. M. Thompson for critical reading of the manuscript, and N. Iijima for technical assistance. This work is supported by NIH grants to A.I. (AI054359 and AI062428) and to C.G. (AI39759 and HL51366). Y.N. was a Japan Society for the Promotion of Science fellow. A.I. is a recipient of the Burroughs Wellcome Investigators in Pathogenesis of Infectious Disease.

Author Contributions Experiments were conceived and designed by Y.N. and A.I. Experiments were performed by Y.N. Data were analysed by Y.N. and A.I. The paper was written by Y.N. and A.I. C.G. and B.L. provided CXCR3-knockout mice and discussed the manuscript.

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Correspondence to Akiko Iwasaki.

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Nakanishi, Y., Lu, B., Gerard, C. et al. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009) doi:10.1038/nature08511

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