Letter | Published:

Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help

Nature volume 533, pages 552556 (26 May 2016) | Download Citation


Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood–brain barrier1 and blood–nerve barrier2, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-γ and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185 (2005)

  2. 2.

    & The blood-nerve barrier: structure and functional significance. Methods Mol. Biol. 686, 149–173 (2011)

  3. 3.

    & Herpes simplex: insights on pathogenesis and possible vaccines. Annu. Rev. Med. 59, 381–395 (2008)

  4. 4.

    & Chromatin control of herpes simplex virus lytic and latent infection. Nature Rev. Microbiol. 6, 211–221 (2008)

  5. 5.

    et al. A mouse model for studies of mucosal immunity to vaginal infection by herpes simplex virus type 2. Lab. Invest. 70, 369–380 (1994)

  6. 6.

    & T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014)

  7. 7.

    , & T lymphocytes are required for protection of the vaginal mucosae and sensory ganglia of immune mice against reinfection with herpes simplex virus type 2. J. Immunol. 160, 6093–6100 (1998)

  8. 8.

    & Immunity to vaginal herpes simplex virus-2 infection in B-cell knockout mice. Immunology 101, 126–131 (2000)

  9. 9.

    et al. Vaginal memory T cells induced by intranasal vaccination are critical for protective T cell recruitment and prevention of genital HSV-2 disease. J. Virol. 88, 13699–13708 (2014)

  10. 10.

    , & Biological properties of herpes simplex virus 2 replication-defective mutant strains in a murine nasal infection model. Virology 278, 137–150 (2000)

  11. 11.

    & FcRn: the neonatal Fc receptor comes of age. Nature Rev. Immunol. 7, 715–725 (2007)

  12. 12.

    , & Mucosal and systemic antiviral antibodies in mice inoculated intravaginally with herpes simplex virus type 2. J. Gen. Virol. 71, 1497–1504 (1990)

  13. 13.

    , & Vaccine-induced serum immunoglobin contributes to protection from herpes simplex virus type 2 genital infection in the presence of immune T cells. J. Virol. 75, 1195–1204 (2001)

  14. 14.

    , , & Spread of herpes simplex virus to the spinal cord is independent of spread to dorsal root ganglia. J. Virol. 85, 3030–3032 (2011)

  15. 15.

    , & Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol. 17, 243–250 (2007)

  16. 16.

    et al. Intravascular staining for discrimination of vascular and tissue leukocytes. Nature Protocols 9, 209–222 (2014)

  17. 17.

    et al. Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins. Mol. Biol. Cell 25, 2710–2719 (2014)

  18. 18.

    , & Viral replication in olfactory receptor neurons and entry into the olfactory bulb and brain. Ann. NY Acad. Sci. 855, 751–761 (1998)

  19. 19.

    et al. Cooperation of B cells and T cells is required for survival of mice infected with vesicular stomatitis virus. Int. Immunol. 9, 1757–1766 (1997)

  20. 20.

    et al. Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus. J. Exp. Med. 205, 3041–3052 (2008)

  21. 21.

    et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014)

  22. 22.

    , , & CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009)

  23. 23.

    et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514–523 (2009)

  24. 24.

    , & Type I IFN suppresses Cxcr2 driven neutrophil recruitment into the sensory ganglia during viral infection. J. Exp. Med. 211, 751–759 (2014)

  25. 25.

    et al. Activated non-neural specific T cells open the blood-brain barrier to circulating antibodies. Brain 122, 1283–1291 (1999)

  26. 26.

    et al. Activated T cells of nonneural specificity open the blood-nerve barrier to circulating antibody. Ann. Neurol. 37, 467–475 (1995)

  27. 27.

    , & Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 329, 1530–1534 (2010)

  28. 28.

    , & Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proc. Natl Acad. Sci. USA 108, 284–289 (2011)

  29. 29.

    , & Effector CD4+ T-cell involvement in clearance of infectious herpes simplex virus type 1 from sensory ganglia and spinal cords. J. Virol. 82, 9678–9688 (2008)

  30. 30.

    et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82, 603–617 (2014)

Download references


We thank H. Dong, S. L. Fink and K. Hashimoto-Torii for animal care support and technical help. We thank R. Medzhitov for discussions. This study was supported by awards from National Institutes of Health grants AI054359, AI062428, AI064705 (to A.I.). A.I. is an investigator of the Howard Hughes Medical Institute.

Author information


  1. Howard Hughes Medical Institute, Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Norifumi Iijima
    •  & Akiko Iwasaki


  1. Search for Norifumi Iijima in:

  2. Search for Akiko Iwasaki in:


N.I. and A.I. planned the project, designed experiments, analysed and interpreted data and wrote the manuscript. N.I. performed experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Akiko Iwasaki.

Extended data

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.