Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection

Alison J. Johnson, Michelle H. Nelson, Melanie D. Bird, Chin Fun Chu, Gregg N. Milligan

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Interferon gamma (IFNγ) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNγ on the development of HSV-specific immune responses and test for IFNγ-independent adaptive immune mechanisms of protection, IFNγ-deficient mice (IFNγ-/-) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk-). HSV-specific cellular and humoral responses were elicited in immunized IFNγ-/- mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8+ T cells from IFNγ-/- mice displayed cytotoxic activity and secreted TNFα. HSV-specific CD4+ T cells from immunized IFNγ-/- mice secreted IL-4, TNFα, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNγ-/- mice produced predominantly IgG1 HSV-specific antibodies while immune B6 mice produced predominantly IgG2c antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNγ-/- mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNγ-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNγ-induced IgG subclasses were more effective once virus had spread to neural tissues.

Original languageEnglish (US)
Pages (from-to)8-15
Number of pages8
JournalJournal of Reproductive Immunology
Volume84
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Fingerprint

Herpes Genitalis
Human Herpesvirus 2
Virus Diseases
Simplexvirus
Interferon-gamma
T-Lymphocytes
Antibodies
Immunoglobulin G
Viruses
Thymidine Kinase
Interleukin-17
Adoptive Transfer
Neurologic Manifestations
Infection
Interleukin-4

Keywords

  • Antibody
  • Female genital tract
  • HSV-2
  • IFNγ
  • IL-17
  • Sensory ganglia

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection. / Johnson, Alison J.; Nelson, Michelle H.; Bird, Melanie D.; Chu, Chin Fun; Milligan, Gregg N.

In: Journal of Reproductive Immunology, Vol. 84, No. 1, 01.2010, p. 8-15.

Research output: Contribution to journalArticle

@article{661958182df346ad84ae2b5e89b21dbf,
title = "Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection",
abstract = "Interferon gamma (IFNγ) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNγ on the development of HSV-specific immune responses and test for IFNγ-independent adaptive immune mechanisms of protection, IFNγ-deficient mice (IFNγ-/-) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk-). HSV-specific cellular and humoral responses were elicited in immunized IFNγ-/- mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8+ T cells from IFNγ-/- mice displayed cytotoxic activity and secreted TNFα. HSV-specific CD4+ T cells from immunized IFNγ-/- mice secreted IL-4, TNFα, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNγ-/- mice produced predominantly IgG1 HSV-specific antibodies while immune B6 mice produced predominantly IgG2c antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to na{\"i}ve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNγ-/- mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNγ-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNγ-induced IgG subclasses were more effective once virus had spread to neural tissues.",
keywords = "Antibody, Female genital tract, HSV-2, IFNγ, IL-17, Sensory ganglia",
author = "Johnson, {Alison J.} and Nelson, {Michelle H.} and Bird, {Melanie D.} and Chu, {Chin Fun} and Milligan, {Gregg N.}",
year = "2010",
month = "1",
doi = "10.1016/j.jri.2009.09.007",
language = "English (US)",
volume = "84",
pages = "8--15",
journal = "Journal of Reproductive Immunology",
issn = "0165-0378",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection

AU - Johnson, Alison J.

AU - Nelson, Michelle H.

AU - Bird, Melanie D.

AU - Chu, Chin Fun

AU - Milligan, Gregg N.

PY - 2010/1

Y1 - 2010/1

N2 - Interferon gamma (IFNγ) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNγ on the development of HSV-specific immune responses and test for IFNγ-independent adaptive immune mechanisms of protection, IFNγ-deficient mice (IFNγ-/-) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk-). HSV-specific cellular and humoral responses were elicited in immunized IFNγ-/- mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8+ T cells from IFNγ-/- mice displayed cytotoxic activity and secreted TNFα. HSV-specific CD4+ T cells from immunized IFNγ-/- mice secreted IL-4, TNFα, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNγ-/- mice produced predominantly IgG1 HSV-specific antibodies while immune B6 mice produced predominantly IgG2c antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNγ-/- mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNγ-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNγ-induced IgG subclasses were more effective once virus had spread to neural tissues.

AB - Interferon gamma (IFNγ) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNγ on the development of HSV-specific immune responses and test for IFNγ-independent adaptive immune mechanisms of protection, IFNγ-deficient mice (IFNγ-/-) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk-). HSV-specific cellular and humoral responses were elicited in immunized IFNγ-/- mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8+ T cells from IFNγ-/- mice displayed cytotoxic activity and secreted TNFα. HSV-specific CD4+ T cells from immunized IFNγ-/- mice secreted IL-4, TNFα, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNγ-/- mice produced predominantly IgG1 HSV-specific antibodies while immune B6 mice produced predominantly IgG2c antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNγ-/- mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNγ-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNγ-induced IgG subclasses were more effective once virus had spread to neural tissues.

KW - Antibody

KW - Female genital tract

KW - HSV-2

KW - IFNγ

KW - IL-17

KW - Sensory ganglia

UR - http://www.scopus.com/inward/record.url?scp=73149123781&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73149123781&partnerID=8YFLogxK

U2 - 10.1016/j.jri.2009.09.007

DO - 10.1016/j.jri.2009.09.007

M3 - Article

C2 - 19942296

AN - SCOPUS:73149123781

VL - 84

SP - 8

EP - 15

JO - Journal of Reproductive Immunology

JF - Journal of Reproductive Immunology

SN - 0165-0378

IS - 1

ER -