Role of two distinct gammadelta T cell subsets during West Nile virus infection.

gammadelta T cells respond rapidly following West Nile virus (WNV) infection, limiting viremia and invasion of the central nervous system and thereby protecting the host from lethal encephalitis. Here, we investigated the role of two major subpopulations of peripheral gammadelta T cells, Vgamma1(+) and Vgamma4(+) cells, in host immunity against WNV infection. We found initially that aged mice were more susceptible to WNV infection than young mice. Following WNV challenge, Vgamma1(+) cells in young mice expanded significantly whereas Vgamma4(+) cells expanded modestly. In contrast, aged mice exhibited a slower and reduced response of Vgamma1(+) cells but maintained a higher content of Vgamma4(+) cells. Vgamma1(+) cells were the major gammadelta subset producing IFN-gamma during WNV infection. Mice depleted of Vgamma1(+) cells had an enhanced viremia and higher mortality to WNV encephalitis. Vgamma4(+) cells had a higher potential for producing tumor necrosis factor-alpha (TNF-alpha), a cytokine known to be involved in blood-brain barrier compromise and WNV entry into the brain. Depletion of Vgamma4(+) cells reduced TNF-alpha level in the periphery, accompanied by a decreased viral load in the brain and a lower mortality to WN encephalitis. These results suggest that Vgamma1(+) and Vgamma4(+) cells play distinct roles in protection and pathogenesis during WNV infection.     

Accumulation of gamma/delta T cells in the lungs and their roles in neutrophil-mediated host defense against pneumococcal infection

The present study was designed to elucidate the role of Vgamma4(+) gammadelta T cells, a major subset of pulmonary gammadelta T cells, in host defense against infection with Streptococcus pneumoniae. The proportion and number of whole gammadelta T cells, identified as CD3(+) and TCR-delta(+) cells, and Vgamma4(+) gammadelta T cells, identified as CD3(+) and TCR-Vgamma4(+) cells, increased in the lungs at 3, 6 and 12h post-infection. Survival of infected mice and lung bacterial clearance were severely impaired in TCR-Vgamma4(-/-) mice compared with control wild-type (WT) mice. The impaired host protection in TCR-Vgamma4(-/-) mice correlated well with attenuated recruitment of neutrophils in lungs. MIP-2 and TNF-alpha synthesis in the infected tissues was significantly reduced in TCR-Vgamma4(-/-) mice compared with WT mice. Similar results were noted in the synthesis of TNF-alpha, but not clearly of MIP-2, by lung leukocytes stimulated with live bacteria. Our results demonstrate that Vgamma4(+) gammadelta T cells play an important role in the neutrophil-mediated host defense against S. pneumoniae infection by promoting the synthesis of TNF-alpha and possibly of MIP-2 in the lungs.     

The interaction of gamma delta T cells with activated macrophages is a property of the V gamma 1 subset

Immunoregulation is an emerging paradigm of gammadelta T cell function. The mechanisms by which gammadelta T cells mediate this function, however, are not clear. Studies have identified a direct role for gammadelta T cells in resolving the host immune response to infection, by eliminating populations of activated macrophages. The aim of this study was to identify macrophage-reactive gammadelta T cells and establish the requirements/outcomes of macrophage-gammadelta T cell interactions during the immune response to the intracellular bacterium, Listeria monocytogenes (Lm). Using a macrophage-T cell coculture system in which peritoneal macrophages from naive or Lm-infected TCRdelta(-/-) mice were incubated with splenocytes from naive and Lm-infected alphabeta/gammadelta T cell-deficient and wild-type mice, the ability to bind macrophages was shown to be restricted to gammadelta T cells and the GV5S1 (Vgamma1) subset of gammadelta T cells. Macrophage adherence resulted in a 4- to 10-fold enrichment of Vgamma1(+) T cells. Enrichment of Vgamma1 T cells was dependent upon the activation status of macrophages, but independent of the activation status of gammadelta T cells. Vgamma1 T cells were cytotoxic for activated macrophages with both the binding to and killing of macrophages being TCR dependent because anti-TCRgammadelta Abs inhibited both Vgamma1 binding and killing activities. These studies establish the identity of macrophage cytotoxic gammadelta T cells, the conditions under which this interaction occurs, and the outcome of this interaction. These findings are concordant with the involvement of Vgamma1 T cells in macrophage homeostasis during the resolution of pathogen-mediated immune responses.     

Fas-Fas ligand interactions are essential for the binding to and killing of activated macrophages by gamma delta T cells

Gammadelta T cells have a direct role in resolving the host immune response to infection by eliminating populations of activated macrophages. Macrophage reactivity resides within the Vgamma1/Vdelta6.3 subset of gammadelta T cells, which have the ability to kill activated macrophages following infection with Listeria monocytogenes (Lm). However, it is not known how gammadelta T cell macrophage cytocidal activity is regulated, or what effector mechanisms gammadelta T cells use to kill activated macrophages. Using a macrophage-T cell coculture system in which peritoneal macrophages from naive or Lm-infected TCRdelta-/- mice were incubated with splenocytes from wild-type and Fas ligand (FasL)-deficient mice (gld), the ability of Vgamma1 T cells to bind macrophages was shown to be dependent upon Fas-FasL interactions. Combinations of anti-TCR and FasL Abs completely abolished binding to and killing of activated macrophages by Vgamma1 T cells. In addition, confocal microscopy showed that Fas and the TCR colocalized on Vgamma1 T cells at points of contact with macrophages. Collectively, these studies identify an accessory or coreceptor-like function for Fas-FasL that is essential for the interaction of Vgamma1 T cells with activated macrophages and their elimination during the resolution stage of pathogen-induced immune responses.     

Depletion of a gamma delta T cell subset can increase host resistance to a bacterial infection

Gammadelta T lymphocytes have been shown to regulate immune responses in diverse experimental systems. Because distinct gammadelta T cell subsets, as defined by the usage of certain TCR V genes, preferentially respond in various diseases and disease models, we have hypothesized that the various gammadelta T cell subsets carry out different functions. To test this, we compared one particular gammadelta T cell subset, the Vgamma1(+) subset, which represents a major gammadelta T cell type in the lymphoid organs and blood of mice, to other subsets and to gammadelta T cells as a whole. Using LISTERIA: monocytogenes infection as an infectious disease model, we found that bacterial containment improves in mice depleted of Vgamma1(+) gammadelta T cells, albeit mice lacking all gammadelta T cells are instead impaired in their ability to control LISTERIA: expansion. Our findings indicate that Vgamma1(+) gammadelta T cells reduce the ability of the innate immune system to destroy LISTERIA:, even though other gammadelta T cells as a whole promote clearance of this pathogen.     

Characterization of lung gamma delta T cells following intranasal infection with Mycobacterium bovis bacillus Calmette-Guérin

The lungs are considered to have an impaired capacity to contain infection by pathogenic mycobacteria, even in the presence of effective systemic immunity. In an attempt to understand the underlying cellular mechanisms, we characterized the gammadelta T cell population following intranasal infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). The peak of gammadelta T cell expansion at 7 days postinfection preceded the 30 day peak of alphabeta T cell expansion and bacterial count. The expanded population of gammadelta T cells in the lungs of BCG-infected mice represents an expansion of the resident Vgamma2 T cell subset as well as an influx of Vgamma1 and of four different Vdelta gene-bearing T cell subsets. The gammadelta T cells in the lungs of BCG-infected mice secreted IFN-gamma following in vitro stimulation with ionomycin and PMA and were cytotoxic against BCG-infected peritoneal macrophages as well as against the uninfected J774 macrophage cell line. The cytotoxicity was selectively blocked by anti-gammadelta TCR mAb and strontium ions, suggesting a granule-exocytosis killing pathway. Depletion of gammadelta T cells by injection of specific mAb had no effect on the subsequent developing CD4 T cell response in the lungs of BCG-infected mice, but significantly reduced cytotoxic activity and IFN-gamma production by lung CD8 T cells. Thus, gammadelta T cells in the lungs might help to control mycobacterial infection in the period between innate and classical adaptive immunity and may also play an important regulatory role in the subsequent onset of alphabeta T lymphocytes.     

V gamma 1+ T cells suppress and V gamma 4+ T cells promote susceptibility to coxsackievirus B3-induced myocarditis in mice

Coxsackievirus B3 infections of C57BL/6 mice, which express the MHC class II IA but not IE Ag, results in virus replication in the heart but minimal myocarditis. In contrast, Bl.Tg.Ealpha mice, which are C57BL/6 mice transgenically induced to express IE Ag, develop significant myocarditis upon Coxsackievirus B3 infection. Despite this difference in inflammatory damage, cardiac virus titers are similar between C57BL/6 and Bl.Tg.Ealpha mice. Removing gammadelta T cells from either strain by genetic manipulation (gammadelta knockout(ko)) changes the disease phenotype. C57BL/6 gammadelta ko mice show increased myocarditis. In contrast, Bl.Tg.Ealpha gammadelta ko mice show decreased cardiac inflammation. Flow cytometry revealed a difference in the gammadelta cell subsets in the two strains, with Vgamma1 dominating in C57BL/6 mice, and Vgamma4 predominating Bl.Tg.Ealpha mice. This suggests that these two Vgamma-defined subsets might have different functions. To test this possibility, we used mAb injection to deplete each subset. Mice depleted of Vgamma1 cells showed enhanced myocarditis, whereas those depleted of Vgamma4 cells suppressed myocarditis. Adoptively transfusing enriched Vgamma4(+) cells to the C57BL/6 and Bl.Tg. Ealpha gammadelta ko strains confirmed that the Vgamma4 subset promoted myocarditis. Th subset analysis suggests that Vgamma1(+) cells biased the CD4(+) T cells to a dominant Th2 cell response, whereas Vgamma4(+) cells biased CD4(+) T cells toward a dominant Th1 cell response.     

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.     

Human V gamma 2V delta 2 T cells augment migration-inhibitory factor secretion and counteract the inhibitory effect of glucocorticoids on IL-1 beta and TNF-alpha production

In immune cells, proinflammatory cytokine gene expression is regulated by glucocorticoids, whereas migration-inhibitory factor (MIF), a pleiotropic cytokine, has the unique property of counteracting the inhibitory effect of glucocorticoids on TNF-alpha and IL-1beta secretion. A few lines of evidence suggest that gammadelta T cells play an important role in immunoregulation. However, it is unknown whether human gammadelta T cells participate in regulating MIF secretion, and how gammadelta T cells, glucocorticoids, and cytokines converge to give a unified physiological response. In this study, we demonstrate that human Vgamma2Vdelta2 T cells augment MIF secretion. Remarkably, these Vgamma2Vdelta2 T cells, functioning similarly to MIF in part, counteracted inhibition of dexamethasone on production of IL-1beta and TNF-alpha. SCID mice reconstituted with human PBMC that were mock depleted of Vdelta2 T cells and repeatedly infected with lethal dose of Escherichia coli had shorter survival time than those reconstituted with PBMC that were depleted of Vdelta2 T cells. Thus, human Vgamma2Vdelta2 T cells are likely to play broad-spectrum roles in immunoregulation and immunopathology by influencing MIF secretion and the immunomodulatory function of glucocorticoids.     

Deficiency of gammadelta T lymphocytes contributes to mortality and immunosuppression in sepsis

Studies have indicated that gammadelta T lymphocytes play an important role in the regulation of immune function and the clearance of intracellular pathogens. We have recently reported that intraepithelial lymphocytes (IEL), which are rich in gammadelta T cells, within the small intestine illustrated a significant increase in apoptosis and immune dysfunction in mice subjected to sepsis. However, the contribution of gammadelta T cells to the host response to polymicrobial sepsis remains unclear. In this study, we initially observed that after sepsis induced by cecal ligation and puncture (CLP), there was an increase in small intestinal IEL CD8+gammadelta+ T cells in control gammadelta+/+ mice. Importantly, we subsequently found an increased early mortality in mice lacking gammadelta T cells (gammadelta-/- mice) after sepsis. This was associated with decreases in plasma TNF-alpha, IL-6, and IL-12 levels in gammadelta-/- mice compared with gammadelta+/+ mice after sepsis. In addition, even though in vitro LPS-stimulated peritoneal macrophages showed a reduction in IL-6 and IL-12 release after CLP, these cytokines were less suppressed in macrophages isolated from gammadelta-/- mice. Alternatively, IL-10 release was not different between septic gammadelta+/+ and gammadelta-/- mice. Whereas T helper (Th)1 cytokine release by anti-CD3-stimulated splenocytes was significantly depressed in septic gammadelta+/+ mice, there was no such depression in gammadelta-/- mice. However, gammadelta T cell deficiency had no effect on Th2 cytokine release. These findings suggest that gammadelta T cells may play a critical role in regulating the host immune response and survival to sepsis, in part by alteration of the level of IEL CD8+gammadelta+ T cells and through the development of the Th1 response.     

Regulatory role of gammadelta T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis

The mechanisms by which T cells accumulate in the lungs of patients with pulmonary fibrosis are poorly understood. Because the lung is continually exposed to microbial agents from the environment, we repeatedly exposed C57BL/6 mice to the ubiquitous microorganism, Bacillus subtilis, to determine whether chronic exposure to an inhaled microorganism could lead to T cell accumulation in the lungs and subsequent pulmonary fibrosis. C57BL/6 mice repeatedly treated with B. subtilis for 4 consecutive weeks developed a 33-fold increase in the number of CD4+ T cells and a 354-fold increase in gammadelta T cells in the lung. The gammadelta T cells consisted almost entirely of Vgamma6/Vdelta1+ cells, a murine subset bearing an invariant TCR the function of which is still unknown. Treatment of C57BL/6 mice with heat-killed vs live B. subtilis resulted in a 2-fold increase in the number of CD4+ T cells in the lung but no expansion of gammadelta T cells indicating that gammadelta cells accumulate in response to live microorganisms. In addition, mice treated with heat-killed B. subtilis developed significantly increased pulmonary fibrosis compared with mice treated with the live microorganism. Mice deficient in Vgamma6/Vdelta1+ T cells when treated with B. subtilis had a 231-fold increase in lung CD4+ T cells and significantly increased collagen deposition compared with wild-type C57BL/6 mice, consistent with an immunoregulatory role for the Vgamma6/Vdelta1 T cell subset. These findings indicate that chronic inhalation of B. subtilis can result in T cell accumulation in the lung and fibrosis, constituting a new model of immune-mediated pulmonary fibrosis.     

Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells

Murine gammadelta T cell subsets, defined by their Vgamma chain usage, have been shown in various disease models to have distinct functional roles. In this study, we examined the responses of the two main peripheral gammadelta T cell subsets, Vgamma1(+) and Vgamma4(+) cells, during collagen-induced arthritis (CIA), a mouse model that shares many hallmarks with human rheumatoid arthritis. We found that whereas both subsets increased in number, only the Vgamma4(+) cells became activated. Surprisingly, these Vgamma4(+) cells appeared to be Ag selected, based on preferential Vgamma4/Vdelta4 pairing and very limited TCR junctions. Furthermore, in both the draining lymph node and the joints, the vast majority of the Vgamma4/Vdelta4(+) cells produced IL-17, a cytokine that appears to be key in the development of CIA. In fact, the number of IL-17-producing Vgamma4(+) gammadelta T cells in the draining lymph nodes was found to be equivalent to the number of CD4(+)alphabeta(+) Th-17 cells. When mice were depleted of Vgamma4(+) cells, clinical disease scores were significantly reduced and the incidence of disease was lowered. A decrease in total IgG and IgG2a anti-collagen Abs was also seen. These results suggest that Vgamma4/Vdelta4(+) gammadelta T cells exacerbate CIA through their production of IL-17.     

Identification of CD25+ gamma delta T cells as fetal thymus-derived naturally occurring IL-17 producers

We previously reported that resident gammadelta T cells in the peritoneal cavity rapidly produced IL-17 in response to Escherichia coli infection to mobilize neutrophils. We found in this study that the IL-17-producing gammadelta T cells did not produce IFN-gamma or IL-4, similar to Th17 cells. IL-17-producing gammadelta T cells specifically express CD25 but not CD122, whereas CD122(+) gammadelta T cells produced IFN-gamma. IL-17-producing gammadelta T cells were decreased but still present in IL-2- or CD25-deficient mice, suggesting a role of IL-2 for their maintenance. IFN-gamma-producing CD122(+) gammadelta T cells were selectively decreased in IL-15-deficient mice. Surprisingly, IL-17-producing gammadelta T cells were already detected in the thymus, although CD25 was not expressed on the intrathymic IL-17-producing gammadelta T cells. The number of thymic IL-17-producing gammadelta T cells was peaked at perinatal period and decreased thereafter, coincided with the developmental kinetics of Vgamma6(+) Vdelta1(+) gammadelta T cells. The number of IL-17-producing gammadelta T cells was decreased in fetal thymus of Vdelta1-deficient mice, whereas Vgamma5(+) fetal thymocytes in normal mice did not produce IL-17. Thus, it was revealed that the fetal thymus-derived Vgamma6(+) Vdelta1(+) T cells functionally differentiate to produce IL-17 within thymus and thereafter express CD25 to be maintained in the periphery.     

Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred gammadelta T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vgamma1+Vdelta5+ gammadelta T cells enhanced AHR. Surprisingly, OVA-specific alphabeta T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses.     

Distinct cytokine-driven responses of activated blood gammadelta T cells: insights into unconventional T cell pleiotropy

Human Vgamma9/Vdelta2 T cells comprise a small population of peripheral blood T cells that in many infectious diseases respond to the microbial metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), expanding to up to 50% of CD3(+) cells. This "transitional response," occurring temporally between the rapid innate and slower adaptive response, is widely viewed as proinflammatory and/or cytolytic. However, increasing evidence that different cytokines drive widely different effector functions in alphabeta T cells provoked us to apply cDNA microarrays to explore the potential pleiotropy of HMB-PP-activated Vgamma9/Vdelta2 T cells. The data and accompanying validations show that the related cytokines, IL-2, IL-4, or IL-21, each drive proliferation and comparable CD69 up-regulation but induce distinct effector responses that differ from prototypic alphabeta T cell responses. For example, the Th1-like response to IL-2 also includes expression of IL-5 and IL-13 that conversely are not induced by IL-4. The data identify specific molecules that may mediate gammadelta T cell effects. Thus, IL-21 induces a lymphoid-homing phenotype and high, unexpected expression of the follicular B cell-attracting chemokine CXCL13/BCA-1, suggesting a novel follicular B-helper-like T cell that may play a hitherto underappreciated role in humoral immunity early in infection. Such broad plasticity emphasizes the capacity of gammadelta T cells to influence the nature of the immune response to different challenges and has implications for the ongoing clinical application of cytokines together with Vgamma9/Vdelta2 TCR agonists.     

IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver

IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4(+) Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6. Interestingly, TCR gammadelta T cells expressing both IFN-gamma and IL-17A were hardly detected, indicating that the IL-17A-producing TCR gammadelta T cells are distinct from IFN-gamma-producing gammadelta T cells, similar to the distinction between Th17 and Th1 in CD4(+) T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR gammadelta T cells, which is important in innate immunity in the liver.     

Evidence that CD8+ dendritic cells enable the development of gammadelta T cells that modulate airway hyperresponsiveness

Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by gammadelta T cells. In mice sensitized and challenged with OVA, AHR depends on allergen-specific alphabeta T cells; but Vgamma1+ gammadelta T cells spontaneously enhance AHR, whereas Vgamma4+ gammadelta T cells, after being induced by airway challenge, suppress AHR. The activity of these gammadelta T cell modulators is allergen nonspecific, and how they develop is unclear. We now show that CD8 is essential for the development of both the AHR suppressor and enhancer gammadelta T cells, although neither type needs to express CD8 itself. Both cell types encounter CD8-expressing non-T cells in the spleen, and their functional development in an otherwise CD8-negative environment can be restored with transferred spleen cell preparations containing CD8+ dendritic cells (DCs), but not CD8+ T cells or CD8- DCs. Our findings suggest that CD8+ DCs in the lymphoid tissues enable an early step in the development of gammadelta T cells through direct cell contact. DC-expressed CD8 might take part in this interaction.     

Production of TNF-alpha by human V gamma 9V delta 2 T cells via engagement of Fc gamma RIIIA, the low affinity type 3 receptor for the Fc portion of IgG, expressed upon TCR activation by nonpeptidic antigen

Human lymphocytes expressing the gammadelta TCR represent a minor T cell subpopulation found in blood. The majority of these cells express Vgamma9Vdelta2 determinants and respond to nonpeptidic phosphoantigens. Several studies have shown that, in vivo, the percentage of Vgamma9Vdelta2 T cells dramatically increases during pathological infection, leading to the hypothesis that they play an important role in the defense against pathogens. However, the specific mechanisms involved in this response remain poorly understood. It has been established that Vgamma9Vdelta2 T cells display potent cytotoxic activity against virus-infected and tumor cells, thereby resembling NK cells. In this study, we show that, upon stimulation by nonpeptidic Ags, Vgamma9Vdelta2 T cells express FcgammaRIIIA (CD16), a receptor that is constitutively expressed on NK cells. CD16 appears to be an activation Ag for Vgamma9Vdelta2 T cells. Indeed, ligation of CD16 on Vgamma9Vdelta2 T cells leads to TNF-alpha production. This TNF-alpha production, which is dependent (like that induced via the TCR-CD3 complex) on the activation of the p38 and extracellular signal-regulated kinase-2 mitogen-activated protein kinases, can be modulated by CD94 NK receptors. Therefore, it appears that Vgamma9Vdelta2 T cells can be physiologically activated by two sequential steps via two different cell surface Ags: the TCR-CD3 complex and the FcgammaRIIIA receptor, which are specific cell surface Ags for T lymphocytes and NK cells, respectively. This strongly suggests that, in the general scheme of the immune response, Vgamma9Vdelta2 T cells represent an important subpopulation of cells that play a key role in the defense against invading pathogens.     

gammadelta T cells contribute to control of chronic parasitemia in Plasmodium chabaudi infections in mice

During a primary infection of mice with Plasmodium chabaudi, gammadelta T cells are stimulated and their expansion coincides with recovery from the acute phase of infection in normal mice or with chronic infections in B cell-deficient mice (mu-MT). To determine whether the large gammadelta T cell pool observed in female B cell-deficient mice is responsible for controlling the chronic infection, studies were done using double-knockout mice deficient in both B and gammadelta cells (mu-MT x delta-/-TCR) and in gammadelta T cell-depleted mu-MT mice. In both types of gammadelta T cell-deficient mice, the early parasitemia following the peak of infection was exacerbated, and the chronic parasitemia was maintained at significantly higher levels in the absence of gammadelta T cells. The majority of gammadelta T cells in C57BL/6 and mu-MT mice responding to infection belonged predominantly to a single family of gammadelta T cells with TCR composed of Vgamma2Vdelta4 chains and which produced IFN-gamma rather than IL-4.