Γδ T-cell Receptor Research Articles

Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation

AbstractThe Stat5 transcription factors Stat5a and Stat5b have been implicated in lymphoid development and transformation. Most studies have employed Stat5a/b-deficient mice where gene targeting disrupted the first protein-coding exon, resulting in the expression of N-terminally truncated forms of Stat5a/b (Stat5a/bΔN/ΔN mice). We have now reanalyzed lymphoid development in Stat5a/bnull/null mice having a complete deletion of the Stat5a/b gene locus. The few surviving Stat5a/bnull/null mice lacked CD8+ T lymphocytes. A massive reduction of CD8+ T cells was also found in Stat5a/bfl/fllck-cre transgenic animals. While γδ T-cell receptor–positive (γδTCR+) cells were expressed at normal levels in Stat5a/bΔN/ΔN mice, they were completely absent in Stat5a/bnull/null animals. Moreover, B-cell maturation was abrogated at the pre–pro-B-cell stage in Stat5a/bnull/null mice, whereas Stat5a/bΔN/ΔN B-lymphoid cells developed to the early pro-B-cell stage. In vitro assays using fetal liver-cell cultures confirmed this observation. Most strikingly, Stat5a/bnull/null cells were resistant to transformation and leukemia development induced by Abelson oncogenes, whereas Stat5a/bΔN/ΔN-derived cells readily transformed. These findings show distinct lymphoid defects for Stat5a/bΔN/ΔN and Stat5a/bnull/null mice and define a novel functional role for the N-termini of Stat5a/b in B-lymphoid transformation.

Alemtuzumab for Refractory Celiac Disease in a Patient at Risk for Enteropathy-Associated T-Cell Lymphoma

To the Editor: A 56-year-old woman had a two-year history of refractory celiac disease for which she had taken prednisone (20 mg per day) for the previous six months, during which time her condition had worsened despite a gluten-free diet. Duodenal biopsy showed severe atrophy with crypt hyperplasia and increased intraepithelial lymphocyte counts. On immunohistochemical analysis, the cytoplasm was positive for CD3 and negative for CD4 and CD8 (Figure 1). Flow-cytometric analysis of intraepithelial lymphocytes showed that more than 50 percent of the cells expressed T-cell receptor γδ (TCRγδ). In addition, we identified a second aberrant population of intraepithelial lymphocytes, . . .

Biology of porcine T lymphocytes

The present review concentrates on the biological aspects of porcine T lymphocytes. Their ontogeny, subpopulations, localization and trafficking, and responses to pathogens are reviewed. The development of porcine T cells begins in the liver during the first trimester of fetal life and continues in the thymus from the second trimester until after birth. Porcine T cells are divided into two lineages, based on their possession of the alphabeta or gammadelta T-cell receptor. Porcine alphabeta T cells recognize antigens in a major histocompatibility complex (MHC)-restricted manner, whereas the gammadelta T cells recognize antigens in a MHC non-restricted fashion. The CD4+CD8- and CD4+CD8lo T cell subsets of alphabeta T cells recognize antigens presented in MHC class II molecules, while the CD4-CD8+ T cell subset recognizes antigens presented in MHC class I molecules. Porcine alphabeta T cells localize mainly in lymphoid tissues, whereas gammadelta T cells predominate in the blood and intestinal epithelium of pigs. Porcine CD8+ alphabeta T cells are a prominent T-cell subset during antiviral responses, while porcine CD4+ alphabeta T cell responses predominantly occur in bacterial and parasitic infections. Porcine gammadelta T cell responses have been reported in only a few infections. Porcine T cell responses are suppressed by some viruses and bacteria. The mechanisms of T cell suppression are not entirely known but reportedly include the killing of T cells, the inhibition of T cell activation and proliferation, the inhibition of antiviral cytokine production, and the induction of immunosuppressive cytokines.

Influences of orally administered lactoferrin on IFN-γ and IL-10 production by intestinal intraepithelial lymphocytes and mesenteric lymph-node cellsThis paper is one of a selection of papers published in this Special Issue, entitled 7th International Conference on Lactoferrin: Structure, Function, and Applications, and has undergone the Journal's usual peer review process.

Intestinal mucosal immunity plays an important role in mucosal and systemic immune responses. We investigated the influences of orally administered bovine lactoferrin (LF) on cytokine production by intestinal intraepithelial lymphocytes (IEL) and mesenteric lymph-node (MLN) cells, especially T cells. Bovine LF or bovine serum albumin (control) was administered to mice once daily for 3 d. After 24 h from the last administration, IEL of the jejunum and ileum and MLN cells were isolated. These cells were cultured with and without the anti-T-cell-receptor antibody, and then the culture supernatants were assayed for cytokines with ELISA. Oral LF did not affect the ratio of T-cell subpopulations in IEL and MLN; however, LF enhanced both interferon (IFN)-gamma and interleukin (IL)-10 production by unstimulated IEL and by IEL stimulated with the alphabeta T-cell receptor but not with the gammadelta T-cell receptor. LF also enhanced both IFN-gamma and IL-10 production by stimulated and unstimulated MLN cells. The production level of IFN-gamma by MLN cells was correlated with that of IL-10. These results suggest that oral LF enhances the production of both Th1-type and Th2/Tr-type cytokines in the small intestine of healthy animals.

IMGT/GeneInfo: T cell receptor gamma TRG and delta TRD genes in database give access to all TR potential V(D)J recombinations.

BackgroundAdaptative immune repertoire diversity in vertebrate species is generated by recombination of variable (V), diversity (D) and joining (J) genes in the immunoglobulin (IG) loci of B lymphocytes and in the T cell receptor (TR) loci of T lymphocytes. These V-J and V-D-J gene rearrangements at the DNA level involve recombination signal sequences (RSS). Whereas many data exist, they are scattered in non specialized resources with different nomenclatures (eg. flat files) and are difficult to extract.DescriptionIMGT/GeneInfo is an online information system that provides, through a user-friendly interface, exhaustive information resulting from the complex mechanisms of T cell receptor V-J and V-D-J recombinations. T cells comprise two populations which express the αβ and γδ TR, respectively. The first version of the system dealt with the Homo sapiens and Mus musculus TRA and TRB loci whose gene rearrangements allow the synthesis of the αβ TR chains. In this paper, we present the second version of IMGT/GeneInfo where we complete the database for the Homo sapiens and Mus musculus TRG and TRD loci along with the introduction of a quality control procedure for existing and new data. We also include new functionalities to the four loci analysis, giving, to date, a very informative tool which allows to work on V(D)J genes of all TR loci in both human and mouse species. IMGT/GeneInfo provides more than 59,000 rearrangement combinations with a full gene description which is freely available at .ConclusionIMGT/GeneInfo allows all TR information sequences to be in the same spot, and are now available within two computer-mouse clicks. This is useful for biologists and bioinformaticians for the study of T lymphocyte V(D)J gene rearrangements and their applications in immune response analysis.

HOW TCRS BIND MHCS, PEPTIDES, AND CORECEPTORS

Since the first crystal structure determinations of alphabeta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gammadelta TCR structures has enabled comparisons of the modes of antigen recognition by alphabeta and gammadelta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3epsilondelta, CD3epsilongamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.

Recognition of pollen-derived phosphatidyl-ethanolamine by human CD1d-restricted γδ T cells

Evidences from mice and human beings indicate that gammadelta T cells could be relevant in recognition of stress-induced self and/or yet unidentified inhaled foreign antigens. Their specificity differs from classic MHC-restricted alphabeta T cells and involves the immunoglobulin-like structure of the gammadelta T-cell receptor with the recognition of small organic molecules, alkylamines, and self lipid compounds presented by CD1+ dendritic cells. Because CD1 receptors are mainly devoted to lipid antigen presentation, we sought to determine whether exogenous pollen membrane lipids may act as allergens for CD1-restricted gammadelta T cells. Peripheral blood and nasal mucosa-associated gammadelta T cells were cloned from normal controls and cypress-sensitive subjects and tested for their antigen specificity and CD1-restriction with phospholipids extracted from tree pollen grains, as well with other natural or synthetic compounds. Phospholipid reactivity of cloned gammadelta T cells was measured by mean of proliferative response and cytokine release as well as by testing their helper activity on IgE production in vitro and in vivo. Cloned gammadelta T lymphocytes from subjects with allergy, but not normal controls, were found to recognize pollen-derived phosphatidyl-ethanolamine (PE) in a CD1d-restricted fashion. Only 16:0/18:2 and 18:2/18:2 PE were stimulatory, whereas no response was recorded for disaturated PE, phosphatidylcholine, neutral lipids, or protein extract. Proliferating clones secreted both T(H)1-type and T(H)2-type cytokines and drove IgE production in vitro and in vivo. CD1d-restricted gammadelta T cells specific for phospholipids can represent a key mucosal regulatory subset for the control of early host reactivity against tree pollens. By knowing how lipid allergen constituents interact with mucosal immune system, we can expand our possibilities in diagnostic and therapeutic interventions.

T Cells of the γδ T-Cell Receptor Lineage Play an Important Role in the Postburn Wound Healing Process

Although gammadelta T cells have been implicated in various aspects of the dermal wound healing process, their role in postburn wound healing processes has not been investigated. To study this, we subjected mice deficient in gammadelta T cells (ie, T-cell receptor delta gene [delta TCR]) and wild-type (WT; C57BL6J) mice to burn injury (25% TBSA) or sham treatment; skin samples were isolated 3 days later. Marked inflammation of the injury site was observed in WT mice but was markedly reduced in delta TCR mice. Postinjury fibroblast growth factor, platelet-derived growth factor granulocyte-colony stimulating factor levels, and nitrite/nitrate were elevated in skin samples from injured WT mice, whereas skin tissue levels of these growth factors and inflammatory mediators was significantly atteunuated in delta TCRmice. In conclusion, these findings support the concept that gammadelta T cells are important to postburn wound healing via the production of growth factors and, potentially, regulation of inducible nitric oxide synthase activation.

Activating Notch1 Mutations Are an Early Event in T-Cell Malignancy of Ikaros Point Mutant Mice.

The Ikaros and Notch1 genes are critical to T-cell formation and differentiation through transcriptional activation of target genes and interaction with chromatin remodeling complexes. Notch1 is a cell surface receptor that is cleaved upon activation to enter the nucleus, and mutated in over 50% of human T-ALL. Ikaros is a zinc finger transcription factor that acts as a homodimer or heterodimer paired with one of several Ikaros family related proteins. Dominant negative Ikaros isoforms generated by alternative splicing activities can induce T-cell tumors in mice and have been reported to participate in the pathogenesis of human T-cell leukemia. An ENU-induced point mutant allele of Ikaros named Plstc which inhibits activity of the normal isoform as well as of other Ikaros family members has been shown to cause a hereditary T-cell lymphoma with autosomal dominant transmission in C57B6 mice. We characterized this disease in heterozygote carriers (Plstc+/−). We now demonstrate for the first time that Notch1 activating mutations are present at a high frequency in the T-cell malignancies that arise in Plstc +/− mice. More than half of Plstc +/− mice developed cervical lymph node enlargement by 4 months of age, with disease-associated mortality close to 100% by 8 months. Pathologic examination revealed massive involvement of the thymus, spleen, liver and kidneys. Peripheral blood smears demonstrated a leukemic phase, but no significant differences in hemoglobin levels or platelet counts. FACS analysis of cervical lymph node tumors revealed a population of lymphocytes overwhelmingly CD3+/T-cell receptorβ+ and minimal CD34, CD117 or T-cell receptorγδ expression. 17% to 63% of T-cells in the samples were CD4+/CD8+, a characteristic of incompletely differentiated thymic lymphocytes, and 36% to 54% of T-cells in samples expressed CD25. Symptomatic lymphoma was preceded by expansion of a CD4+/CD8+ T cell population in the peripheral blood by 10 weeks of age and as early as 8 weeks. This is earlier than reported for other dominant negative forms of Ikaros which do not alter activity of Ikaros related family members. Mutation analysis of Notch1 in Plstc+/− T-cell lymphomas revealed the presence of activating mutations in Notch1 in 9 of 15 cases (60%), analogous to those reported in human T-ALL samples. In these cases, the isolated lymph node predominantly contained either an exon 26 point mutation within the activating cleavage domain, or an exon 34 insertion leading to a frameshift and early truncation of the C-terminal PEST domain. By contrast, DNA isolated from lymph nodes of wild type littermates and DNA isolated from tail tips of each mouse by 5 weeks of age did not contain Notch1 mutations consistent with a somatically acquired oncogenic event. The predominance of Notch1 mutations in the tumors of Plstc+/− mice shows that preferential interactions between Notch1 and Ikaros family members can be a significant early event in T-cell proliferation and tumorigenesis, and provides a mouse model for further defining interactions between the Ikaros and Notch1 oncoproteins in the pathogenesis of T-cell tumors.

Vδ1 T cell receptor binds specifically to MHC I chain related A: Molecular and biochemical evidences

Human MHC class I chain-related A (MICA) is a tumor-associated antigen that can be recognized by Vδ1 subset of tumor-infiltrating γδ T cells. We previously reported that immobilized recombinant MICA protein could induce the proliferation of tumor-infiltrating Vδ1 γδ T cells in vitro. But there has been no direct evidence showing the engagement of γδ T cell receptors (TCR) of the induced cells with MICA. In the current investigation, we show that MICA induces specific cytolytic activity of the expanded γδ T cells. We expressed the coupled V domains from the MICA-induced T cells as a single polypeptide chain VδVγ TCR (γδ scTCR). Such scTCR can specifically bind MICA of HeLa cells. Direct interaction of γδ scTCRs with in vitro expressed MICA was monitored using an IAsys biosensor. We found that the Vδ1 scTCR can specifically bind to immobilized MICA molecule and MICAα1α2 domains are responsible for the binding reaction.

Remission of pure red cell aplasia in T-cell receptor γδ-large granular lymphocyte leukemia after therapy with low-dose alemtuzumab

Remission of pure red cell aplasia in T-cell receptor γδ -large granular lymphocyte leukemia after therapy with low-dose alemtuzumab

Effects of Age and Nutrition on Expression of CD25, CD44, and l-Selectin (CD62L) on T-cells from Neonatal Calves

Effects of the plane of nutrition and age on the proliferation and activation of lymphocyte subsets from milk replacer-fed calves were investigated in vitro. Holstein calves were fed a standard (0.45kg/d of a 20% crude protein, 20% fat milk replacer, n=4) or intensified (1.14kg/d of a 28% crude protein, 20% fat milk replacer, n=4) diet from 1 to 8wk of age. Average daily weight gain of intensified-diet (0.66kg/d) calves was greater than that of standard-diet (0.27kg/d) calves. Relative to the pokeweed mitogen-induced responses of CD4+ cells from steers (5 to 6 mo of age), CD4+ cells from 1-wk-old calves showed decreased proliferative activity, delayed increase in CD25 expression, and no demonstrable increase in CD44 expression or decrease in CD62L expression. Calf CD8+ and γδT-cell receptor+ cells, unlike T-cells from the older animals, did not demonstrate decreased expression of CD62L after stimulation with mitogen. The increased expression of CD44 by mitogen-stimulated γδT-cell receptor+ cells from older animals was not seen in γδT-cell receptor+ cells from 1-wk-old calves. At wk 8 of age, mitogen-induced proliferation and expression of activation antigens by T-cells from standard-fed calves were similar to responses of T-cells from steers indicating rapid maturation of T-cell function during the neonatal period. Feeding calves an intensified milk replacer was associated with decreased proliferation of mitogen-stimulated CD4+, CD8+, and γδT-cell receptor+ cells; decreased CD25 expression by mitogen-stimulated CD4+ and CD8+ cells; and decreased CD44 expression by mitogen-stimulated CD8+ cells. These results indicate that the functional capacity of the calf's T-cell population becomes more adult-like during the first weeks of life and suggest that nutrition modulates T-cell function during this period of immune maturation.

Expanding the Professional Cell Staff

Antigen-presenting cells (APCs) chew up proteins and offer the resulting fragments of peptide, along with a suite of stimulatory molecules, to cells of the αβ T cell receptor (TCR) lineage to produce activated T cells armed and ready to clear the corresponding infection. Few cell types are known to be potent "professional" APCs, and at the very top of the stack are dendritic cells (DCs). Brandes et al. (see the Perspective by Modlin and Sieling) now expand this realm to include a subset of nonconventional human T cells bearing the γδ TCR. These cells react vigorously to microbial stimulation and, when induced to do so in cell culture, became extremely efficient at presenting different types of antigen to their αβ T cell counterparts. The cells appeared to traffic antigen to the same cellular compartments as DCs and up-regulated an equivalent array of stimulatory and homing molecules. As well as contributing directly to innate immunity, γδ T cells may also represent important instigators of adaptive immune responses. M. Brandes, K. Willimann, B. Moser, Professional antigen-presentation function by human γδ T cells. Science 309 , 264-268 (2005). [Abstract] [Full Text] R. L. Modlin, P. A. Sieling, Now presenting: γδ T cells. Science 309 , 252-253 (2005). [Summary] [Full Text]

Structure of a γδ T Cell Receptor in Complex with the Nonclassical MHC T22

Gammadelta T cell receptors (TCRs), alphabeta TCRs, and antibodies are the three lineages of somatically recombined antigen receptors. The structural basis for ligand recognition is well defined for alphabeta TCR and antibodies but is lacking for gammadelta TCRs. We present the 3.4 A structure of the murine gammadelta TCR G8 bound to its major histocompatibility complex (MHC) class Ib ligand, T22. G8 predominantly uses germline-encoded residues of its delta chain complementarity-determining region 3 (CDR3) loop to bind T22 in an orientation substantially different from that seen in alphabeta TCR/peptide-MHC. That junctionally encoded G8 residues play an ancillary role in binding suggests a fusion of innate and adaptive recognition strategies.

Antigen Recognition Determinants of γδ T Cell Receptors

The molecular basis of gammadelta T cell receptor (TCR) recognition is poorly understood. Here, we analyze the TCR sequences of a natural gammadelta T cell population specific for the major histocompatibility complex class Ib molecule T22. We find that T22 recognition correlates strongly with a somatically recombined TCRdelta complementarity-determining region 3 (CDR3) motif derived from germ line-encoded residues. Sequence diversity around these residues modulates TCR ligand-binding affinities, whereas V gene usage correlates mainly with tissue origin. These results show how an antigen-specific gammadelta TCR repertoire can be generated at a high frequency and suggest that gammadelta T cells recognize a limited number of antigens.

Heat shock protein induced TCR γδ gene rearrangements in patients with oral cancer

We analyzed the T cell receptor (TCR) gammadelta gene repertoire in peripheral blood and tumor compartment of oral cancer (OC) patients before and after stimulation with heat shock proteins (hsp), which are known ligands for gammadelta T cells. Clonal TCR gamma and delta gene rearrangements in lymphocytes from tumor compartment and peripheral blood were studied using TCR Vgamma and Vdelta gene primers in PCR followed by heteroduplex analysis. Vgamma gene segments derived from VgammaI or VgammaII gene families were most dominantly expressed in peripheral blood lymphocytes (PBL) as compared to tumor infiltrating lymphocytes (TIL) of OC patients. Of the rearranged TCR delta alleles Vdelta1-Jdelta1 and Vdelta2-Jdelta1 gene rearrangements were the most predominant in PBL and TIL of OC patients respectively. Stimulation of gammadelta T cells with hsp 60/70 demonstrated a selective clonal expansion of Vgamma9-Vdelta2 (VgammaII family) subset indicating that, this expanded population of cells could be responsible for eliciting an immune response against oral tumor cells.

The evolutionary and structural ‘logic’ of antigen receptor diversity

Most vertebrate species utilize antibody and T-cell receptor (TCR) genes to create a vast repertoire of antigen sensor molecules on their B and T lymphocytes, respectively. While the organization of these genes exhibits substantial variation between species, one common theme is that, in almost every case, there is at least one variable region with a highly diverse CDR3 region and often much less diversity elsewhere in the binding site. Whereas with αβ TCRs this skewing of diversity correlates well with the need to recognize diverse peptides bound to MHC molecules, this cannot explain why this same pattern is evident in immunoglobulins (Igs) or γδ TCRs. Instead we have postulated that in the primary repertoire, all or most antigen receptors have a bipartite binding site, in which diverse CDR3 loops act as a highly antigen specific ‘core’ whereas other CDRs bind in a largely opportunistic fashion. In the case of antibodies, somatic hypermutation then acts to improve the complementarity to a given antigen and increase antibody affinity. A test of this model in mice engineered to have a very limited V region repertoire shows that primary antibodies can be generated that are highly specific for distinct antigens, yet identical in sequence except for their V H CDR3. Furthermore, very high affinity antibodies can be raised by repeated immunizations, showing that somatic hypermutation can mold these low affinity antibodies into high affinity ones. Thus, the wide variations seen in V region repertoires amongst vertebrates is likely to be of lesser importance than the preservation of one or more diverse CDR3 regions.

Gamma interferon production by bovine gamma delta T cells following stimulation with mycobacterial mycolylarabinogalactan peptidoglycan.

A large percentage of lymphocytes in the blood of cattle express the gamma delta T-cell receptor, but specific functions for these cells have not yet been clearly defined. There is evidence, however, that human, murine, and bovine gamma delta T cells have a role in the immune response to mycobacteria. This study investigated the ability of bovine gamma delta T cells to expand and produce gamma interferon (IFN-gamma) in response to stimulation with mycobacterial products. Bovine gamma delta T cells, isolated from the peripheral blood of healthy cattle, expanded following in vitro stimulation with live mycobacteria, mycobacterial crude cell wall extract, and Mycobacterium bovis culture filtrate proteins. In addition, purified gamma delta T cells, cocultured with purified monocytes and interleukin-2, consistently produced significant amounts of IFN-gamma in response to mycobacterial cell wall. The IFN-gamma-inducing component of the cell wall was further identified as a proteolytically resistant, non-sodium dodecyl sulfate-soluble component of the mycolylarabinogalactan peptidoglycan.

NK and NKT cell functions in immunosenescence.

Immunosenescence is defined as the state of dysregulated immune function that contributes to the increased susceptibility to infection, cancer and autoimmune diseases observed in old organisms, including humans. However, dysregulations in the immune functions are normally counterbalanced by continuous adaptation of the body to the deteriorations that occur over time. These adaptive changes are likely to occur in healthy human centenarians. Both innate (natural) and adaptive (acquired) immune responses decline with advancing age. Natural killer (NK) and natural killer T (NKT) cells represent the best model to describe innate and adaptive immune response in aging. NK and NKT cell cytotoxicity decreases in aging as well as interferon-gamma (IFN-gamma) production by both activated cell types. Their innate and acquired immune responses are preserved in very old age. However, NKT cells bearing T-cell receptor (TCR) gammadelta also display an increased cytotoxicity and IFN-gamma production in very old age. This fact suggests that NKT cells bearing TCRgammadelta are more involved in maintaining innate and adaptive immune response in aging leading to successful aging. The role played by the neuroendocrine-immune network and by nutritional factors, such as zinc, in maintaining NK and NKT cell functions in aging is discussed.

T-cell-mediated mechanisms involved in resolution of genital herpes simplex virus type 2 (HSV-2) infection of mice

Resolution of a HSV-2 infection of the female genital tract has been shown to be T-cell dependent. The T-cell populations and mechanisms involved in clearance of virus from the genital epithelium were examined in this study. T lymphocytes expressing either αβ or γδ T-cell receptors (TCR) have been detected in the vaginal epithelium of mice. The involvement of γδ T cells in HSV-2 clearance was tested by intravaginal (ivag) challenge of mice depleted of αβ T cells by administration of specific antibodies and of mice lacking γδ T cells due to specific deletion of the δ TCR gene. The results of these studies strongly suggest that γδ T cells are not required for or involved in clearance of HSV-2 from the genital epithelium. Mechanisms of virus clearance employed by αβ T cells were also examined. Although HSV-specific lytic activity could be demonstrated ex vivo in populations of vaginal exudate cells from HSV-infected mice, clearance of virus did not require either perforin- or Fas/Fas ligand (FasL)-dependent cytolytic pathways. In contrast, virus resolution was significantly impaired following neutralization of interferon-gamma (IFN-γ), but not tumor necrosis factor-alpha (TNF-α). Together, these results suggest that non-lytic mechanisms mediated by αβ T cells were responsible for resolution of a genital HSV-2 infection.