Immunology Letters 147 (2012) 34–40 Contents lists available at SciVerse ScienceDirect Immunology Letters j ourna l h o me page: www.elsevier.com/locate/immlet Pathological effect of IL-17A-producing TCR + T cells in mouse genital mucosa against HSV-2 infection Jae-Ouk Kim 1 , Hye-Ran Cha, Eun-Do Kim, Mi-Na Kweon ∗ Mucosal Immunology Section, Laboratory Science Division, International Vaccine Institute, Seoul National University Research Park, Kwanak-Gu, Seoul 151-919, Republic of Korea a r t i c l e i n f o Article history: Received 12 January 2012 Received in revised form 24 April 2012 Accepted 31 May 2012 Available online 12 June 2012 Keywords: IL-17A TCR + T cells Genital tract HSV-2 a b s t r a c t Interleukin (IL)-17A is a cytokine that plays an important role in infectious, autoimmune, and inflam- matory diseases. In this study, we found that TCR + CD4 - CD8 - T cells, but not TCR + CD4 + T cells, are the primary producers of IL-17A in the genital tract of female mice in the steady-state condition. High mRNA levels of IL-17A and RORt were determined in TCR + T cells isolated from mouse genital tract but lacked detectable expression of IFN, T-bet, and FoxP3. IL-17A production by genital TCR + T cells was maintained after intravaginal vaccination with cholera toxin or avirulent herpes simplex virus type (HSV)-2 186 syn TK strain. Of note, the deaths of IL-17A -/- mice were significantly delayed after intravaginal HSV-2 infection compared with wild-type mice. Further, genital TCR + T cells continued to produce comparable amounts of IL-17A after antibiotic treatment. These results imply that genital IL- 17A-producing TCR + T cells constitutively exist at steady state and that they play a pathogenic effect against HSV-2 infection and are not affected by microflora, unlike conventional Th17 cells. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Interleukin (IL)-17A was initially cloned from activated T cells with 57% homology to the protein encoded by T lymphotropic her- pesvirus (HSV) saimiri gene 13 and named CTLA-8 [1,2]. To date, six IL-17 members (A, B, C, D, E, and F) have been identified in the mouse family [3]. Of these, IL-17F has the highest homology with IL-17A; both are mainly produced by activated CD4 + T cells that are classified as Th17 cells [4–6]. The orphan nuclear receptor RORt is a key transcription factor that induces transcription of the genes encoding IL-17A and IL-17F in naïve CD4 + T helper cells and is required for their expression in response to IL-6 and TGF-, the cytokines known to induce IL-17 [7]. IL-17A exerts proinflammatory effects by induction of TNF-, IL- 1, IL-6, CXC chemokines, and other chemoattractants, recruiting neutrophils and other immune cells [8]. IL-17A is thought to have a protective role in host defense against extracellular pathogens such as fungi and bacteria, while it has pathological aspects in organ- specific autoimmune diseases [9]. Several studies have addressed Abbreviations: AhR, arylhydrocarbon receptor; CT, cholera toxin; HSV-2, her- pes simplex virus type 2; MNCs, mononuclear cells; Th17, T helper type 17; MPA, medroxyprogesterone 17-acetate. ∗ Corresponding author. Tel.: +82 2 881 1153; fax: +82 2 881 1211. E-mail address: mnkweon@ivi.int (M.-N. Kweon). 1 Present address: Neonatal Vaccinology Section, Laboratory Science Division, International Vaccine Institute, Seoul, Republic of Korea. the relationship between IL-17 and viral infections [10–13]; however, its exact role in modulating immune response against viral infection in the mucosal site, which is the first line of defense, has not been fully elucidated. Although CD4 + T cells are major sources of IL-17A upon anti- gen stimulation, current studies show that IL-17A can be produced by innate lymphocytes such as NK cells, NKT cells, and TCR + T cells [14,15]. TCR + T cells, which constitute only a minor subset in the systemic compartments, are disproportionately enriched at mucosal tissues with a restricted repertoire of the variable region of the T cell receptor [16]. The role of TCR + T cells has been eluci- dated in epithelial homeostasis and recruitment of inflammatory cells to sites of tissue damage [17,18]. Although TCR + T cell- deficient mice are resistant to Listeria monocytogenes challenges, they show substantial alterations in patterns of immunopathology [19–21]. In contrast, TCR + T cells have a protective role against HSV type 1 infection in a mouse model [22]. In the present study, we found that TCR + CD4 - CD8 - T cells are the major population of IL-17A-secreting cells in the female genital tract of mice at the steady state. TCR + T cells in the genital tract exhibit different expression profiles of cytokines and transcrip- tion factors compared to those from spleen. Here, we attempted to examine cytokine production by genital tract TCR + T cells in response to vaginal vaccination with toxin- or viral-based vaccines and antibiotic treatment. Of note, TCR + T cells did not produce IFN and maintained IL-17A production under all experimental conditions. These findings suggest that IL-17A-producing TCR + T cells in the genital tract have unique characteristics. 0165-2478/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.imlet.2012.05.006