Age-related functional decline of human B cells.

This study aimed to investigate the changes in B cell functional decline and antigen sensitization with aging using two Epstein Barr virus (EBV)-immortalized human B cell lines, one from a 22-year-old man (EBV-B young) and the other from a 65-year-old man (EBV-B old). The activity of senescence-associated ß-galactosidase, a marker of cellular senescence, was enhanced in the EBV-B old cells compared with EBV-B young cells. Moreover, the levels of p16, p21, IL-6, TNF-α, and TGF-ß1, which are senescence-associated secretary phenotypes, were also increased in EBV-B old cells. In vitro immunization of EBV-B cells with ß-lactoglobulin further showed that EBV-B old cells had a reduced cell population of naïve B cells than that of EBV-B young cells. Furthermore, HLA-DR expression, which is important for antigen presentation, was decreased in the EBV-B old cells. Comparative microarray analysis between EBV-B young and old cells also showed decreased expression of antibody genes, such as those of the heavy chain and light chain (κ chain). These results suggest that cellular senescence and decreased gene expression are responsible, at least in part, for the decline in B cell function and antigen sensitization capacity with aging, which ultimately impairs the function of the acquired immune system.

IL-12 protects from psoriasiform skin inflammation.

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis.

Differentiation of CD11c+ CX3CR1+ cells in the small intestine requires Notch signaling.

The gastrointestinal tract comes into direct contact with environmental agents, including bacteria, viruses, and foods. Intestine-specific subsets of immune cells maintain gut homeostasis by continuously sampling luminal antigens and maintaining immune tolerance. CD11c(+)CX3CR1(+) cells sample luminal antigens in the small intestine and contribute to the trafficking of bacteria to lymph nodes under dysbiotic conditions. The molecular mechanisms crucial for the differentiation of CD11c(+)CX3CR1(+) cells remain unclear. Here we demonstrate that the Notch1- or Notch2-Rbpj axis is essential for the development of CD11c(+)CX3CR1(+) cells. In mice in which Rbpj or Notch1 and Notch2 were deleted from CD11c(+) cells, there was a deficit of CD11c(+)CX3CR1(+) cells and an accumulation of CD11c(low)CX3CR1(+) cells. The CD11c(low)CX3CR1(+) cells could not differentiate to CD11c(+)CX3CR1(+) cells, suggesting that CD11c(low)CX3CR1(+) cells represent a lineage distinct from CD11c(+)CX3CR1(+) cells. These data indicate that Notch signaling is essential for lineage fixation of intestinal CD11c(+)CX3CR1(+) cells.

Anti-Proliferative Activities and Apoptosis Induction by Triterpenes Derived from Eriobotrya japonica in Human Leukemia Cell Lines.

Eriobotrya japonica leaf is a traditional herbal medicine that contains numerous triterpenes, which have various pharmacological properties. In this study, we investigated the anti-proliferative activity of four triterpenes derived from E. japonica, including corosolic acid (CA), ursolic acid (UA), maslinic acid (MA) and oleanolic acid (OA), in human leukemia cell lines. CA showed the strongest anti-proliferative activity in all of the leukemia cell lines tested, but not in normal human skin fibroblast cell lines. To determine the mechanism underlying the anti-proliferative effect of CA, we examined the effect of CA on molecular events known as apoptosis induction. CA induced chromatin condensation, DNA fragmentation, sub-G(1) phase DNA, activation of caspase-3, -8 and -9 and the cleavage of PARP in HL-60. CA also activated Bid and Bax, leading to the loss of mitochondrial membrane potential (∆ψ(m)) and cytochrome c release into the cytosol, whereas Bcl-2 and Bcl-xL were unaffected by CA. These results suggest that CA has an anti-proliferative effect on leukemia cells via the induction of apoptosis mediated by mitochondrial dysfunction and caspase activation. CA may be a potential chemotherapeutic agent for the treatment of human leukemia.

Manipulation of CD98 resolves type 1 diabetes in nonobese diabetic mice.

The interplay of CD4(+) and CD8(+) T cells targeting autoantigens is responsible for the progression of a number of autoimmune diseases, including type 1 diabetes mellitus (T1D). Understanding the molecular mechanisms that regulate T cell activation is crucial for designing effective therapies for autoimmune diseases. We probed a panel of Abs with T cell-modulating activity and identified a mAb specific for the H chain of CD98 (CD98hc) that was able to suppress T cell proliferation. The anti-CD98hc mAb also inhibited Ag-specific proliferation and the acquisition of effector function by CD4(+) and CD8(+) T cells in vitro and in vivo. Injection of the anti-CD98hc mAb completely prevented the onset of cyclophosphamide-induced diabetes in NOD mice. Treatment of diabetic NOD mice with anti-CD98hc reversed the diabetic state to normal levels, coincident with decreased proliferation of CD4(+) T cells. Furthermore, treatment of diabetic NOD mice with CD98hc small interfering RNA resolved T1D. These data indicate that strategies targeting CD98hc might have clinical application for treating T1D and other T cell-mediated autoimmune diseases.

Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung.

Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A-dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6 were identified as the major IL-17A-producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A-producing TCR gammadelta T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A-producing TCR gammadelta T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR gammadelta T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.

Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.

CD4(+) helper T (Th) cells differentiate toward distinct effector cell lineages characterized by their distinct cytokine expression patterns and functions. Multiple Th cell populations secrete IL-22 that contributes to both protective and pathological inflammatory responses. Although the differentiation of IL-22-producing Th cells is controlled by the aryl hydrocarbon receptor (AhR), little is known about the regulatory mechanisms inducing physiological stimulators for AhR. Here, we show that Notch signaling enhances IL-22 production by CD4(+) T cells by a mechanism involving AhR stimulation. Notch-mediated stimulation of CD4(+) T cells increased the production of IL-22 even in the absence of STAT3. CD4(+) T cells from RBP-J-deficient mice had little ability to produce IL-22 through T cell receptor-mediated stimulation. RBP-J-deficient mice were highly susceptible to the detrimental immunopathology associated with ConA-induced hepatitis with little IL-22 production by CD4(+) T cells. Exogenous IL-22 protected RBP-J-deficient mice from ConA-induced hepatitis. Notch signaling promoted production of endogenous stimulators for AhR, which further augmented IL-22 secretion. Our studies identify a Notch-AhR axis that regulates IL-22 expression and fine-tunes immune system control of inflammatory responses.

Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction.

Natural killer (NK) cells regulate various immune responses by exerting cytotoxic activity or secreting cytokines. The interaction of NK cells with dendritic cells (DC) contributes to NK cell-mediated antitumor or antimicrobial responses. However, the cellular and molecular mechanisms for controlling this interaction are largely unknown. Here, we show an involvement of Jagged2-Notch interaction in augmenting NK cell cytotoxicity mediated by DC. Enforced expression of Jagged2 on A20 cells (Jag2-A20 cells) suppressed their growth in vivo, which was abrogated by depleting NK cells. Moreover, Jag2-A20 cells exerted a suppression on the growth of nonmanipulated A20 cells in SCID mice in an NK-dependent manner. Consistently, coinoculation of A20 cells with DC overexpressing Jagged2 (Jag2-DC) suppressed the growth of A20 cells in mice. Stimulation of NK cells with Jagged2 directly enhanced their cytotoxicity, IFN-gamma production, and proliferation. Ligation of Notch2 on NK cells enhanced their cytotoxic activity, and Jag2-DC or CpG-treated DC-mediated NK cell cytotoxicity was suppressed by a gamma-secretase inhibitor. These results indicate that the Jagged2-Notch axis plays a crucial role in DC-mediated NK cell cytotoxicity. Furthermore, manipulation of this interaction may provide an approach to induce potent tumor immunity or to inhibit certain autoimmune diseases caused by NK cell activation.

Importance of murine Vdelta1gammadelta T cells expressing interferon-gamma and interleukin-17A in innate protection against Listeria monocytogenes infection.

Murine gammadelta T cells participate in the innate immune response against infection by an intracellular pathogen Listeria monocytogenes. Vdelta1+gammadelta T cells coexpressing Vgamma6 are a major gammadelta T-cell subpopulation induced at an early stage of L. monocytogenes infection in the livers of infected mice. To investigate the protective role of the Vgamma6/Vdelta1+gammadelta T cells against L. monocytogenes infection, Vdelta1 gene-deficient (Vdelta1-/-) mice were analysed because these mice selectively lacked a Vgamma6/Vdelta1+gammadelta T-cell subpopulation in the L. monocytogenes-infected liver. The Vdelta1-/- mice showed increased bacterial burden in the liver and spleen, and decreased survival rate at an early stage of L. monocytogenes infection when compared to wild-type mice. Histological examination showed abscess-like lesions and unorganized distribution of macrophages in the liver of the Vdelta1-/- mice but not in the wild-type mice after L. monocytogenes infection. The Vgamma6/Vdelta1+gammadelta T cells produced interferon-gamma and interleukin-17A. All the results suggest that murine Vgamma6/Vdelta1+gammadelta T cells control the innate protective response against L. monocytogenes infection through production of the proinflammatory cytokines interferon-gamma and interleukin-17A in the infected liver.

Vdelta1+ T cells are crucial for repertoire formation of gammadelta T cells in the lung.

The pulmonary resident T lymphocytes (RPLs) expressing a nearly invariant T cell receptor gammadelta heterodimer (gammadeltaTCR) migrate from fetal thymus to the lung epithelium, followed by RPL subsets expressing diverse sets of gammadeltaTCRs after birth. However, it remains unclear whether the fetal type Vgamma6/Vdelta1+ RPLs are essential for gammadelta T cell repertoire formation in the lung epithelium. In this study, we found a marked decrease in the number of gammadeltaRPLs at 4 weeks of age in Vdelta1-/- mice and they predominantly expressed Vgamma6 and Vdelta4 genes. The skewed diversity towards the Vdelta4-(Ddelta1)-Ddelta2-Jdelta2 junctional region was observed only in gammadelta RPLs from 4-week-old Vdelta1-/- mice, compared with those from 8-week-old Vdelta1-/- mice and the both ages of wild-type mice. These results suggest that the invariant Vdelta1+ T cells are crucial not only for optimal gammadelta T cell expansion but also for affecting the migration or microenvironment for other gammadelta T cells in the lung epithelium.

Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterised by dysregulation of autoreactive lymphocytes and antigen-presenting cells. Signalling through Toll-like receptor 9 (TLR9), a mediator of innate immune responses, has a role in activation of dendritic cells and autoreactive B cells. OBJECTIVE: To investigate whether TLR9 polymorphisms are associated with an increased risk of SLE. METHODS: DNA samples were obtained from 220 Japanese patients with SLE (with >4 American College of Rheumatology criteria for SLE) and 203 controls. The genetic variations of TLR9 were detected by PCR, followed by DNA sequencing. The promoter and enhancer activities of TLR9 were measured by luciferase reporter gene assay. The titres of anti-dsDNA antibodies in sera from control or TLR9-deficient mice were analysed by ELISA. RESULTS: The G allele at position +1174 (located in intron 1 of TLR9) is closely associated with an increased risk of SLE (p = 0.029). Furthermore, patients with SLE tend to have C allele at position -1486 (p = 0.11). Both alleles down regulate TLR9 expression by reporter gene assay. TLR9-deficient mice under a C57BL/6 background possess higher titres of anti-dsDNA serum antibodies than control C57BL/6 mice. CONCLUSIONS: These results indicate that the presence of the G allele at position +1174 of TLR9 predisposes humans to an increased risk of SLE. It is speculated that TLR9 normally prevents the development of human SLE.

Resident Vdelta1+ gammadelta T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production.

Neutrophils infiltrate the site of infection and play critical roles in host defense, especially against extracellular bacteria. In the present study, we found a rapid and transient production of IL-17 after i.p. infection with Escherichia coli, preceding the influx of neutrophils. Neutralization of IL-17 resulted in a reduced infiltration of neutrophils and an impaired bacterial clearance. Ex vivo intracellular cytokine flow cytometric analysis revealed that gammadelta T cell population was the major source of IL-17. Mice depleted of gammadelta T cells by mAb treatment or mice genetically lacking Vdelta1 showed diminished IL-17 production and reduced neutrophil infiltration after E. coli infection, indicating an importance of Vdelta1(+) gammadelta T cells as the source of IL-17. It was further revealed that gammadelta T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23, which was induced rapidly after E. coli infection in a TLR4 signaling-dependent manner. Thus, although gammadelta T cells are generally regarded as a part of early induced immune responses, which bridge innate and adaptive immune responses, our study demonstrated a novel role of gammadelta T cells as a first line of host defense controlling neutrophil-mediated innate immune responses.

Lunatic fringe controls T cell differentiation through modulating notch signaling.

T cells differentiate from bone marrow-derived stem cells by expressing developmental stage-specific genes. We here searched arrays of genes that are highly expressed in mature CD4-CD8+ (CD8 single-positive (SP)) T cells but little in CD4+CD8+ (double-positive (DP)) cells by cDNA subtraction. Lunatic fringe (Lfng), a modulator of Notch signaling, was identified to be little expressed in DP cells and highly expressed in CD8SP T cell as well as in CD4-CD8- (double-negative (DN)) and mature CD4+CD8- (CD4SP) T cells. Thus, we examined whether such change of expression of Lfng plays a role in T cell development. We found that overexpression of Lfng in Jurkat T cells strengthened Notch signaling by reporter gene assay, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cells development due to the defective transition from CD44+CD25- stage to subsequent stage in DN cells. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggested that the physiological high expression of Lfng in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling. Shutting down the expression of Lfng in DP cells may have a physiological role in promoting DP cells differentiation toward mature SP cells.

Involvement of CD45 in central nervous system myelination.

Myelin is a multi-layered membranous lipid insulator surrounding axons that allows the rapid conduction of neuronal impulses. In the central nervous system (CNS), myelin is produced by oligodendrocytes. During development, morphologically immature oligodendrocyte precursor cells (OPCs) arise from neural stem cells before differentiating into myelinating oligodendrocytes shortly after birth. Fyn tyrosine kinase (Fyn) has been shown to play a central role during OPC differentiation, including inducing morphological changes in the cells and initiating the expression of myelin basic protein (MBP), a major structural protein required for the compaction of myelin sheaths. Recently, we have shown that signaling via the gamma chain of immunoglobulin Fc receptors (FcRgamma) induces the Fyn-MBP cascade and promotes the morphological differentiation of OPCs. The protein tyrosine phosphatases that are responsible for the positive regulation of Fyn tyrosine kinase activity during this cascade, however, remained unknown. Here we report that a protein tyrosine phosphatase, CD45, is involved in this process. Fyn co-immunoprecipitated with CD45 from differentiating wild-type OPCs in vitro, while CD45-deficient OPCs failed to differentiate. Additionally, dysmyelination was observed in CD45-deficient mice in vivo. Our findings suggest that CD45 is a key phosphatase involved in OPC differentiation and provide a preliminary explanation for the previously reported CD45 mutations observed in some multiple sclerosis (MS) patients.

Oral administration of bovine colostrum stimulates intestinal intraepithelial lymphocytes to polarize Th1-type in mice.

Th1 stimulus for Th2-skewed immune response during infancy is important for reduction of incidence of allergic diseases. We examined effects of oral administration of bovine colostrum on local immunity in intestine in adult mice. C57BL/6 mice were orally given bovine colostrum or control milk for 1, 3 or 6 months and intestinal microflora, fecal IgA, and lymphocyte population of gut-associated lymphoid tissues and their abilities of cytokine production were examined. Although the cell populations of intestinal intraepithelial lymphocytes (i-IEL) were not remarkably changed, the T cells in i-IEL were polarized to Th1 type after oral administration of bovine colostrum. Intestinal microflora and IgA levels in feces were not changed by oral administration of bovine colostrum. These results suggest that colostrum stimulates directly to i-IEL to polarize Th1 type, which may protect from infectious diseases and allergic diseases mediated by Th2 type responses.

Vdelta1+ gammadelta T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice.

An influx of neutrophils followed a short time later by an influx of macrophages to the infected site plays a key role in innate immunity against Escherichia coli infection. We found in this study that Vdelta1-/- mice exhibited impaired accumulation of peritoneal macrophages but not neutrophils and delayed bacterial clearance after i.p. inoculation with E. coli. Peritoneal gammadelta T cells from E. coli-infected wild-type mice produced CCL3/MIP-1alpha and CCL5/RANTES in response to gammadelta TCR triggering in vitro, whereas such production was not evident in gammadelta T cells from E. coli-infected Vdelta1-/- mice. Neutralization of CCL3/MIP-1alpha by a specific mAb in vivo significantly inhibited the accumulation of macrophages in the peritoneal cavity after E. coli infection, resulting in exacerbated bacterial growth in the peritoneal cavity. These results suggest that Vdelta1+ gammadelta T cells bridge a gap between neutrophils and macrophages in innate immunity during E. coli infection mediated by production of CC chemokines, enhancing macrophage trafficking to the site of infection.

Effective treatment of a mouse model of Sjögren's syndrome with eyedrop administration of anti-CD4 monoclonal antibody.

OBJECTIVE: To determine whether eyedrop administration of an anti-CD4 monoclonal antibody (mAb) is effective in the treatment of Sjögren's syndrome (SS) using a mouse model of the disease. METHODS: The anti-CD4 mAb was administered daily into the eyes of mice with SS from ages 4 to 8 weeks or ages 10 to 12 weeks. During treatment, tear volume was monitored and after final treatment, histologic features of the lacrimal and salivary glands, the phenotypes and function of T cells, and serum titers of anti-alpha-fodrin antibody were examined. RESULTS: Eyedrop administration of anti-CD4 mAb before the onset of SS prevented the autoimmune pathology seen in the lacrimal glands but not that in the salivary glands. Furthermore, eyedrop administration of anti-CD4 mAb after the development of SS inhibited mononuclear cell infiltration and the destruction of parenchyma only in the lacrimal glands. Eyedrop administration of anti-CD4 mAb suppressed the local activation of CD4+ T cells rather than deleting CD4+ T cells, which reduced the expansion of pathologic CD4+ T cells against alpha-fodrin. CONCLUSION: These results demonstrate the remarkable efficacy of anti-CD4 mAb eyedrops in the treatment of SS eye symptoms, which illustrates a new antibody-based therapeutic strategy for patients with eye problems caused by SS as well as other diseases.

Donor-specific tolerance induced by simultaneous allogeneic islet transplantation with CD4+CD25+ T-cells into hepatic parenchyma in mice.

BACKGROUND: The allogeneic islets transplantation is an ideal therapeutic strategy for patients with diabetes mellitus. However, it has been difficult to induce immunological tolerance against islets grafts. The CD4+CD25+ regulatory T-cells (Treg) play a role in suppressing T-cell activation. Thus, we evaluated whether Treg can regulate donor-specific T-cell tolerance that received allogeneic islets into the hepatic parenchyma (ITxHP) along with Treg. METHODS: C3H/He mice were used as donors; and streptozotocin-induced diabetic BALB/c mice were recipients. The protocol included three groups: Group A recipients received only 300 IE islets; Group B was given 300 IE islets and whole splenocytes; Group C was given 300 IE islets and Treg purified from peripheral lymph nodes. RESULTS: For all mice in Groups A and B, the fasting blood sugar exceeded 250mg/dl and graft rejection was observed. GVHD was observed earlier in Group B than in Group A. In contrast graft survival exceeded 30 days for two mice in Group C (50%, mean POD 28.5 +/- 24.0, P<0.05). Mixed lymphocyte reaction showed that T-cells from tolerant mice had very weak responses against spleen cells from C3H mice. CONCLUSIONS: The simultaneous ITxHP with CD4+CD25+ T-cells administration prolonged islet graft survivals and induced donor-specific hyporesponsiveness.

The critical role of Fas-Fas ligand interaction in donor-specific transfusion-induced tolerance to H-Y antigen.

BACKGROUND: Donor-specific transfusion (DST) has been clinically used to enhance the survival of transplanted organs, and it has been shown in mice to induce tolerance to male (H-Y) antigen (Ag). Although the biologic mechanisms that initiate and maintain DST-induced tolerance involve clonal deletion, induction of anergy, and generation of regulatory cells, the molecules essential to tolerance induction are still unclear. In this study, we investigated the role of Fas-FasL interaction in DST-induced tolerance to H-Y Ag. METHODS: C57BL/6 (B6) or B6-Fas(lpr) (lpr) female mice were intravenously injected with B6, lpr, or B6-FasL(gld) (gld) male spleen cells (SC). B6 male skin grafts, mixed lymphocyte reaction (MLR) assay, and cytotoxicity assay (CTL) were performed 7 days after DST. In some experiments, purified B-cells were used as transfused cells. RESULTS: B6 female mice treated with B6 male SC permanently accepted B6 male skins, whereas untreated B6 or lpr female mice rejected B6 male skins. On the other hand, B6 female mice treated with gld male SC acceleratingly rejected male skin, as did lpr female mice treated with B6 or gld male SC. The recipient mice in the experimental groups, in which DST resulted in the accelerated rejection of the skin grafts, had strong allo-responses to H-Y Ag in MLR and CTL. Further, B6 female mice treated with gld male B-cells acceleratingly rejected male skins, whereas B6 female mice treated with B6 or lpr male B-cells from mice accepted male skins. CONCLUSIONS: These findings suggest that the interaction between FasL upon infused SC, especially upon B-cells and Fas in a recipient, is essential in DST-induced tolerance to H-Y Ag.

Intraepithelial gammadelta T cells may bridge a gap between innate immunity and acquired immunity to herpes simplex virus type 2.

Mice depleted of gammadelta T cells by in vivo administration of anti-TCRgammadelta monoclonal antibodies showed susceptibility against an intravaginal infection with herpes simplex virus type 2 (HSV-2). The systemic Th1 response was impaired in the gammadelta T-cell-depleted mice. Mice deficient in the Vdelta1 T subset were susceptible to an intravaginal infection with HSV-2. Intraepithelial gammadelta T cells bearing Vdelta1 may help protect against intravaginal infection with HSV-2 through promoting the systemic Th1 response.