The homogeneity of the TCRδ repertoire expressed by the Thy-1dull γ δ T cell population is due to cellular selection

Thy-1^dull γ δ T cells are an unusual subset of mature TCRγ δ T cells characterized by their highly restricted TCR repertoire. In DBA/2 mice, they predominantly express the product of the Vγ1 gene together with that of a member of the Vδ6 subfamily (the Vδ6.4 gene) and their junctional sequences show very little diversity. To address the mechanisms underlying the expression of the restricted TCRγ δ repertoire, we have cloned all Vδ6 subfamily members present in DBA/2 mice and studied their frequency of expression in Thy-1^dull and Thy-1^bright γ δ thymocyte populations. Furthermore, we have also cloned non-functional Vδ6DδJδ1 rearrangements present in the Thy-1^dull γ δ T cell population and compared their Vδ6 gene utilization and their junctional sequences with those expressed by this population. Our results indicate that the restricted TCRδ repertoire expressed by the Thy-1^dull γ δ thymocytes results from cellular selection, rather than molecular constraints suggesting the existence of a limited set of self-ligands. Finally, phenotypic, functional and TCRγ δ repertoire analysis of Thy-1^dull γ δ T cells in β2 -microglobulin (β₂m)-deficient mice indicated that these putative ligands are not β₂m-dependent major histocompatibility complex class I or class I-like molecules.     

Mechanisms determining cell membrane expression of different γδ TCR chain pairings

We investigated the ability of the most common TCR‐γ and δ chains to express on the cell surface. Vγ1Cγ4 and Vγ7Cγ1 chains paired with all TCR‐δ chains tested, whereas Vγ4Cγ1 chains were found with Vδ4 and Vδ5, but not with Vδ2 or Vδ6 chains, and Vγ2Cγ2 chains were expressed only with Vδ5. Mapping studies showed that up to four polymorphic residues influence the different co‐expressions of Vγ1 and Vγ2 chains with Vδ chains. Unexpectedly, these residues are not located in the canonical γ/δ interface, but in the outer part of the γδ TCR complex exposed to the solvent. Expression of functional Vδ4 or Vδ6 chains in Vγ2/Vδ5⁺ cells or of functional Vγ2Cγ2 in Vγ1⁺ cells reduced cell‐surface expression of the γδ TCR. Taken together, these data show that (i) the Vγ/Vδ repertoire of mouse γδ T cells is reduced by physical constraints in their associations. (ii) Lack of Vγ2/Vδ expression is due to the formation of aberrant TCR complexes, rather than to an intrinsic inability of the chains to pair and (iii) despite not being expressed at the cell surface, the presence of a functionally rearranged Vγ2 chain in γδ T cells results in reduced TCR levels.     

Different cytokine production profiles of γδ T cell clones: Relation to inflammatory arthritis

This study was performed to investigate whether γδ T cells could also be divided into subsets, identified by a cytokine profile, as described for αβ T helper (Th) cell subsets. Cytokine production was studied in 22 γδ T cell clones obtained from the synovial fluid and peripheral blood of one patient with inflammatory arthritis and compared to that of 26 αβ T cell clones of the same and different patients. Interferon-γ (IFN-γ) was produced by 18 (82%) and interleukin-4 (IL-4) by 17 (77%) out of 22 γδ T cell clones, respectively. In contrast, IL-10 was not produced, except at very low level in one case. The mean levels of IL-4 were lower for clones derived from synovial fluid. When considering the production of IFN-γ as an indicator of Th1 and that of IL-4 as an indicator of Th2, respectively, the most common pattern was a γδTh1-like pattern, with the combination of high levels of IFN-γ and low levels of IL-4. This pattern was found in Vδ1⁺ clones, all from synovial fluid. Additional patterns were also observed: a mixed, probably γδ Th0-like pattern with a more balanced production of both IFN-γ and IL-4; a γδTh1 pattern with the production of IFN-γ alone; a γδTh2 pattern with the production of IL-4 alone. These three patterns were also seen in blood γδ T cells which were all Vδ2, indicating that these patterns were independent of the γδ phenotype. γδ T cell clones produced lower levels of IFN-γ (p = 0.001) and higher levels of IL-4 than αβ clones (p < 0.02). These differences in cytokine production between αβ and γδ subsets and within these subsets may contribute to their respective role in chronic inflammation.     

Impaired survival of T cell receptor Vγ3+ cells in interleukin-4 transgenic mice

The mouse epidermis contains a network of Thy-1⁺ dendritic T cells. Most of these cells express a homogeneous T cell receptor (TCR) configuration (Vγ3/ Vδ1) with only negligible junctional diversity. Because fetal thymocytes are precursors of these dendritic epidermal T cells (DETC) and the addition of interleukin (IL)-4 to fetal thymic organ cultures causes an early arrest in thymopoiesis, we examined DETC development in transgenic (tg) mice expressing IL-4 under the control of major histocompatibility complex class I regulatory sequences. Immunohistologic examination of epidermal sheets and polymerase chain reaction analysis of total skin RNA from IL-4 tg mice failed to reveal TCR Vγ3⁺ DETC and Vγ3 mRNA, respectively. In contrast, the sizes of TCR γδ subpopulations in lymphoid organs were unchanged in these mice. Although the numbers and staining intensities of TCR Vγ3⁺ thymocytes in early fetal (days 14–17) IL-4 tg mice were similar to those of littermate controls, we observed a preferential death of these cells in thymic organ cultures from IL-4 tg mice. We observed further that epidermal sheets prepared from 9-day-old mice whose mothers had been treated with an IL-4-neutralizing antibody from day 12 to day 18 of pregnancy contained DETC numbers similar to those of controls. However, upon termination of the anti-IL-4 treatment, DETC ceased to expand. We conclude that IL-4 impairs the survival of TCR Vγ3⁺ cells.     

Characteristics of fetal thymus-derived T cell receptor γδ intestinal intraepithelial lymphocytes

We have previously demonstrated that grafting of CBF1(H-2^b/d) fetal thymus (FTG) under the kidney capsule of congenitally athymic nude mice of BALB/c background (H-2^d) generates a substantial number of T cell receptor (TCR) γδ intestinal intraepithelial lymphocytes (IEL) that were of FTG origin (H-2^b+) (see accompanying report). Here we investigated the characteristics of these FTG-derived TCR γδ IEL and compared them to the extrathymically derived TCR γδ IEL found in nude mice. Phenotypically, FTG-derived TCR γδ IEL were similar to their extrathymically derived counterparts in that most were Thy-1 ^?, CD5^? and CD8αα (homodimer). Vγ and Vδ gene usage in thymus-derived and extrathymically derived TCR γδ IEL were found to be virtually the same. Functionally, FTG-derived TCR γδ IEL were similar to the TCR γδ IEL found in euthymic mice as both were relatively anergic to TCR cross-linking in vitro. However, FTG-derived TCR γδ IEL differed slightly from extrathymically derived TCR γδ IEL, which were completely nonresponsive to the same in vitro stimulation. Overall, these findings support the view that FTG-derived and extrathymically derived TCR γδ IEL are almost indistinguishable. Lastly, we demonstrate that despite their thymic origin, development of FTG-derived TCR γδ IEL partially takes place extrathymically; that is positive selection of FTG-derived Vδ4 IEL occurs extrathymically. In addition, we demonstrate that the CD8 molecule is not necessary for development and homing of FTG-derived TCR γδ IEL. This later finding suggests that the CD8αα molecule develops extrathymically for FTG-derived CD8αα TCR γδ IEL.     

T cell receptor γδ repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive γδ clones

To study the relevance of γδ T cells in multiple sclerosis (MS) we analyzed the T cell receptor (TCR) γδ repertoire and the antigen reactivity of γδ clones isolated from cerebrospinal fluid (CSF). In T cell cultures derived from CSF we found an increased percentage of Vδ1⁺ cells as compared to peripheral blood of the same donors. Phenotypic analysis of cells from MS CSF with Vγ- and Vγ-specific monoclonal antibodies (mAb) showed that the Vγ1 chain is most frequently associated with γ chains belonging to the VγI family. Sequence analysis of TCR genes revealed heterogeneity of junctional regions in both δ and γ genes indicating polyclonal expansion. γδ clones were established and some recognized glioblastoma, astrocytoma or monocytic cell lines. Stimulation with these targets induced serine esterase release and lymphokine expression characteristic of the T_H0-like phenotype. Remarkably, these tumor-reactive γδ cells were not detected in the peripheral blood using PCR oligotyping, but were found in other CSF lines independently established from the same MS patient. Altogether, these results demonstrate that in the CSF there is a skewed TCR γδ repertoire and suggest that γδ cells reacting against brain-derived antigens might have been locally expanded.     

Evidence that productive rearrangements of TCR γ genes influence the commitment of progenitor cells to differentiate into αβ or γδ T cells

Two models have been considered to account for the differentiation of γδ and αβ T cells from a common hematopoietic progenitor cell. In one model, progenitor cells commit to a lineage before T cell receptor (TCR) rearrangement occurs. In the other model, progenitor cells first undergo rearrangement of TCRγ, δ, or both genes, and cells that succeed in generating a functional receptor commit to the γδ lineage, while those that do not proceed to attempt complete β and subsequently α gene rearrangements. A prediction of the latter model is that TCRγ rearrangements present in αβ T cells will be nonproductive. We tested this hypothesis by examining Vγ2-Jγ1Cγ1 rearrangements, which are commonly found in αβ T cells. The results indicate that Vγ2-Jγ1Cγ1 rearrangements in purified αβ T cell populations are almost all nonproductive. The low frequency of productive rearrangements of Vγ2 in αβ T cells is apparently not due to a property of the rearrangement machinery, because a transgenic rearrangement substrate, in which the Vγ2 gene harbored a frame-shift mutation that prevents expression at the protein level, was often rearranged in a productive configuration in αβ T cells. The results suggest that progenitor cells which undergo productive rearrangement of their endogenous Vγ2 gene are selectively excluded from the αβ T cell lineage.     

Interleukin-15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing γδ T cell receptor in mice

Several cytokines including stem cell factor (SCF) and interleukin (IL)-7 are known to be required for development of γδ T cell receptor (TCR) intestinal intraepithelial lymphocytes (i-IEL) in mice. We show here the effects of IL-15 on the proliferation and maintenance of murine γδ i-IEL in vitro. γδ i-IEL constitutively expressed a high level of IL-15 receptor α mRNA and proliferated in response to IL-15 more vigorously than αβ i-IEL. Vγ/δ repertoire analysis revealed that IL-15, like IL-2, induced polyclonal expansion of γδ i-IEL, whereas γδ i-IEL responding to IL-7 showed a Vγ/δ repertoire skewed towards Vγ1/Vδ4, Vδ5. IL-15 efficiently prevented γδ i-IEL from apoptosis induced by growth factor deprivation. This rescue was accompanied by up-regulation of Bcl-2 expression. These results suggest that IL-15 plays important roles in proliferation and maintenance of γδ i-IEL.     

Preferentially expanding Vγ1+ γδ T cells are associated with protective immunity against Plasmodium infection in mice

γδ T cells play a crucial role in controlling malaria parasites. Dendritic cell (DC) activation via CD40 ligand (CD40L)‐CD40 signaling by γδ T cells induces protective immunity against the blood‐stage Plasmodium berghei XAT (PbXAT) parasites in mice. However, it is unknown which γδ T‐cell subset has an effector role and is required to control the Plasmodium infection. Here, using antibodies to deplete TCR Vγ1⁺ cells, we saw that Vγ1⁺ γδ T cells were important for the control of PbXAT infection. Splenic Vγ1⁺ γδ T cells preferentially expand and express CD40L, and both Vγ1⁺ and Vγ4⁺ γδ T cells produce IFN‐γ during infection. Although expression of CD40L on Vγ1⁺ γδ T cells is maintained during infection, the IFN‐γ positivity of Vγ1⁺ γδ T cells is reduced in late‐phase infection due to γδ T‐cell dysfunction. In Plasmodium‐infected IFN‐γ signaling‐deficient mice, DC activation is reduced, resulting in the suppression of γδ T‐cell dysfunction and the dampening of γδ T‐cell expansion in the late phase of infection. Our data suggest that Vγ1⁺ γδ T cells represent a major subset responding to PbXAT infection and that the Vγ1⁺ γδ T‐cell response is dependent on IFN‐γ‐activated DCs.     

Control of self-reactive cytotoxic T lymphocytes expressing γδ T cell receptors by natural killer inhibitory receptors

The majority of peripheral blood γδ T cells in human adults expresses T cell receptors (TCR) with identical V regions (Vγ9 and Vδ2). These Vγ9Vδ2 T cells recognize the major histocompatibility complex (MHC) class I-deficient B cell line Daudi and broadly distributed nonpeptidic antigens present in bacteria and parasites. Here we show that unlike αβ or Vγ9^? γδ T cells, the majority of Vγ9Vδ2T cells harbor natural killer inhibitory receptors (KIR) (mainly CD94/NKG2A heterodimers), which are known to deliver inhibitory signals upon interaction with MHC class I molecules. Within Vγ9δ2 T cells, KIR were mainly expressed by clones exhibiting a strong lytic activity against Daudi cells. In stark contrast, almost all Vγ9Vδ2 T cell clones devoid of killing activity were KIR^?, thus suggesting a coordinate acquisition of KIR and cytotoxic activity within Vγ9Vδ2 T cells. In functional terms, KIR inhibited lysis of MHC class I-positive tumor B cell lines by Vγ9Vδ2 cytotoxic T lymphocytes (CTL) and raised their threshold of activation by microbial antigens presented by MHC class I-positive cells. Furthermore, masking KIR or MHC class I molecules revealed a TCR-dependent recognition by Vγ9Vδ2 CTL of ligands expressed by activated T lymphocytes, including the effector cells themselves. Taken together, these results suggest a general implication of Vγ9Vδ2 T cells in immune response regulation and a central role of KIR in the control of self-reactive γδ CTL.     

Comparative analysis of αβ and γδ T cell activation by Mycobacterium tuberculosis and isopentenyl pyrophosphate

Phosphorylated nonpeptide compounds have recently been identified as potent mycobacteria-derived ligands for human Vγ9/Vδ2-expressing γδ T cells. Crude mycobacterial extracts also contain protein antigens which stimulate CD4 αβ T cells to produce growth factors that are used by γδ T cells for clonal expansion. We have investigated the dynamics in vitro of expansion of CD4 T cells and Vγ9 cells in cultures of peripheral blood mononuclear cells stimulated with synthetic isopentenyl pyrophosphate (IPP) in the absence or presence of additional stimuli. The results indicated that following stimulation with IPP, γδ T cells express CD25 and CD69 antigens, but fail to proliferate unless growth factors are provided exogenously or endogenously through activation of CD4 T cells by additional stimuli such as tetanus toxoid, alloantigen, or superantigens. Furthermore, the presence of antigen presenting cells are required for expansion of γδ T cells. In response to IPP stimulation, purified CD4 T cells neither express CD25 or CD69, nor do they proliferate even in the presence of exogenous IL-2. Apart from IL-2, IL-15 and, less efficiently, IL-4, IL-7, and IL-12 can contribute to cellular expansion of IPP-reactive Vγ9 cells. Together, the results demonstrate that peripheral blood γδ T cells proliferate in response to IPP only if CD4 T cells are simultaneously activated by an additional stimulus. This mechanism provides a tight control of the reactivity of γδ T cells towards phosphorylated nonpeptide antigens.     

γδ T cells come to stay: Innate skin memory in the Aldara model

The term immunological memory has long been a trademark restricted to adaptive lymphocytes such as memory B cells and plasma cells as well as memory CD8⁺ αβ T cells. In recent years, innate lymphocytes such as NK cells have also been shown to adapt to their environment by antigen‐specific expansion and selective survival. However, whether γδ T cells mount comparable memory responses to pathogenic stimuli is less well understood. In this issue of European Journal of Immunology, Hartwig et al. [Eur. J. Immunol. 2015. 45: 3022–3033] identify a subset of IL‐17‐producing γδ T cells that are capable of establishing long‐lived memory in the skin of mice exposed to imiquimod in the Aldara psoriasis model. These γδ T cells uniformly express a Vγ4⁺Vδ4⁺ TCR. They produce IL‐17A/F and persist in the dermis for long periods of time, also at untreated distal sites. Upon secondary challenge, experienced Vγ4⁺Vδ4⁺ cells show enhanced effector functions and mediate exacerbated secondary inflammation. These findings showcase innate γδ T‐cell memory that uses a single conserved public TCR combination. Furthermore, they provide mechanistic insight to the observed psoriatic relapses in patients in response to topical treatment with imiquimod.     

Development of γδ T cells in the adult murine thymus

The development of T cells belonging to the γδ lineage is not well understood. We have analyzed the cells in the adult murine thymus which express the γδ TcR on the surface in order to learn more about this process. Our data demonstrate a number of clear subpopulations of γδ expressing cells in the thymus based on the expression of Thy-1 and HSA (heat-stable antigen). Only one of these subpopulations, the one expressing both Thy-1 and HSA, contains dividing cells or has a significant rate of turnover. Together with the fact that emigrant γδ cells are HSA⁺Thy-1⁺, this suggests that this thymic subpopulation is the sole, or major, source of exported cells. However, the turnover of cells from this population is 5 × 10⁴ - 10 × 10⁴ cells per day, while previous estimates of the rate of export of γδ cells are in the order of 10⁴ cells per day. Furthermore the Vγ profile of recent γδ⁺ emigrants differs from that of the thymic HSA⁺Thy-1⁺ cells. This raises the possibility that only a selected subpopulation of the thymic γδ⁺HSA⁺Thy-l⁺ population is exported, and that some γδ cells may die in situ in the thymus. The function of the other γδ thymic subpopulations, which are turning over very slowly or not at all, (i.e. the HAS^?Thy-l^? and HAS^?Thy-l⁺ subpopulations) remains unclear.     

The surface epithelium of recurrent infected palatine tonsils is rich in γδ T cells

Using a large panel of MoAbs in quantitative morphometric analysis of immunohistochemically stained tissue sections, we compared the frequency and distribution of immune cells in palatine tonsils from patients with recurrent tonsillitis (RT) and patients with idiopathic tonsillar hypertrophy (ITH). We found that differences between the two patient groups in leucocyte populations were limited to the surface epithelium, whereas the cellular composition of interfollicular and follicular areas was similar. Most intraepithelial lymphocytes were CD8⁺ T cells in both groups. However, the number of intraepithelial T cells was significantly higher in RT compared with ITH. This was due to a selective increase in the number of intraepithelial CD8⁺γδ T cells utilizing Vδ1 and Vγ9. In both patient groups the majority of the intraepithelial γδ T cells expressed Vδ1 and Vγ9. Subepithelially, γδ T cells utilizing Vγ9 dominated over cells utilizing Vγ8, while equal proportions expressed Vδ1 and Vδ2. These results suggest that cells utilizing the otherwise rare combination Vδ1/Vγ9 in their T cell receptors (TCR) may constitute a major γδ T cell population in palatine tonsils and are probably reactive to antigens specific to the tonsillar milieu. Furthermore, they indicate that preferentially this γδ T cell subpopulation is involved in immune reactions within the surface epithelium in RT. We speculate that γδ T cells are involved in clearing infectious bacteria at the tonsillar surface and in limiting inflammatory responses in the tonsils. Both local expansion and infiltration of blood cells probably contribute to the high numbers of γδ T cells in RT patients.     

Mycobacteria-reactive γδ T cells in HIV-infected individuals: lack of Vγ9 cell responsiveness is due to deficiency of antigen-specific CD4 T helper type 1 cells

Human γδ T lymphocytes expressing the variable T cell receptor elements Vγδ paired with Vδ2 are activated by antigen derived from Mycobacterium tuberculosis (M. tb.) and presented by antigen-presenting cells (APC). The subsequent proliferation is strictly dependent on the presence of CD4⁺TCRαβ⁺ T helper type 1 (Th1) cells producing interleukin-2 (IL-2). In this study, we report that the reactivity of Vγ9 cells to M. tb. stimulation in vitro was drastically decreased or absent in the majority of the analyzed HIV-1-infected individuals (CDC stages III and IV). We show that the failure of Vγ9 cells frim HIV^? individuals to proliferate following M. tb. stimulation was not due to an intrinsic qualitative or quantitative defect of γδ T cells but rather to a deficiency of M. tb.-reactive CD4 Th1 cells. Thus, Vγ9 responsiveness could be restored if cultures of M. tb.-stimulated T cells from HIV⁺ donors were reconstituted with one of the following: (i) exogenous IL-2; (ii) purified CD4T cells from allogeneic donors; or (iii) T cell-depleted APC from allogeneic donors. In the majority of HIV⁺ patients, the defective Th1 activity of M. tb.-stimulated CD4 T cells could be increased neither by cytokines known to favor Th1 development (IL-12, interferon-γ) nor by neutralization of the Th1-suppressing Th2 cytokine IL-10. We suggest that measurement of Vγ9 cell expansion within M. tb.-stimulated peripheral blood mononuclear cells provides a sensitive assay for the functional capacity of antigen (M. tb.)-specific CD4 Th1 cells in HIV-infected individuals.     

Expression of pro-inflammatory cytokines by TCRαβ+ T and TCRγδ+ T cells in an experimental model of colitis

An inflammatory bowel disease (IBD) comparable to human ulcerative colitis is induced upon transfer of T cell-depleted wild-type (F1) bone marrow into syngeneic T cell-deficient (tgε26) mice (F1 → tgε26). Previously we have shown that activated CD4⁺ T cells predominate in transplanted tgε26 mice, and adoptive transfer experiments verified the potential of these cells to cause disease in immunodeficient recipient mice. Using flow cytometry for the detection of intracellular cytokine expression, we demonstrate in the present study that large numbers of CD4⁺ and CD8⁺ TCRαβ⁺ T cells from the intraepithelial region and lamina propria of the colon of diseased, but not from disease-free mice, produced interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Large numbers of T cells from peripheral lymphoid tissues of these animals also expressed IFN-α and TNF-α, but few expressed interleukin-4, demonstrating g strong bias towards Th1-type T cell responses in these animals. TCRγδ⁺ T cells, typically minor constituents of the inflammatory infiltrate of the colon in F1 → tgε26 mice, also expressed IFN-γ at a high frequency upon CD3 stimulation. In light of these findings we examined the potential involvement of TCRγδ⁺ T cells by testing their ability to induce colitis in tgε26 mice. We report here that tgε26 mice transplanted with T cell-depleted bone marrow from TCRα^null and TCRβ^null animals developed IBD. Furthermore, disease in these mice correlated with the development of peripheral and colonic TCRαδ⁺ T cells capable of IFN-γ production. These results suggest that IFN-γ may be a common mediator of IBD utilized by pathogenic T cells of distinct phenotype.     

Phosphoantigen activation induces surface translocation of intracellular CD94/NKG2A class I receptor on CD94− peripheral Vγ9 Vδ2 T cells but not on CD94− thymic or mature γ δ T cell clones

Most adult peripheral blood γ δ T cells express Vγ9/Vδ2-encoded TCR that recognize a restricted set of nonpeptidic phosphorylated compounds, referred to as phosphoantigens. They also express various MHC class I-specific inhibitory receptors (IR), in particular CD94/NKG2-A heterodimers, which participate in the fine tuning of their TCR-mediated activation threshold. Most mature Vγ9/Vδ2 T cells express surface CD94 receptors, unlike cord blood or thymus-derived Vγ9/Vδ2 clones, thus suggesting a role for the microenvironment in IR expression. In the present study we show that most CD94⁻ Vγ9Vδ2 PBL ex vivo express an intracellular pool of CD94/NKG2-A receptors that is translocated to the cell surface upon activation by phosphoantigens or IL-2. In stark contrast, intracellular CD94/NKG2-A complexes are undetectable in CD94⁻ thymus or PBL-derived mature Vδ2 T cell clones, and no surface induction is observed following phosphoantigen activation of T cell clones. Altogether these results provide new insights into the regulation of CD94/NKG2-A expression on T lymphocytes and suggest the existence of distinct mechanisms controlling in vivo and in vitro induction of IR on these cells.     

Control of B cell lymphoma recognition via natural killer inhibitory receptors implies a role for human Vγ9/Vδ2 T cells in tumor immunity

The Vγ9/Vδ2 T cell receptor (TCR) is expressed by most human γδ T cells. We show here that cytotoxic T lymphocytes of the Vγ9/Vδ2 subset, but not of the Vδ1 subset of human γδ T cells, express natural killer inhibitory receptors (KIR) with specificity for different HLA class I alleles that down-regulate TCR-mediated signaling in response to HLA class I-expressing B cell lymphomas. Vγ9/Vδ2 T cell clones with a T helper cell phenotype lack KIR and produce lymphokines in response to most human B cell lymphomas, just as they do upon recognition of the HLA class l-deficient human Burkitt's lymphoma Daudi. Thus, human Vγ9/Vδ2 T cells have an innate specificity for nonpolymorphic cell surface structures expressed by many lymphoma cells and their cytotoxic activity is controlled by KIR. These results imply a general role of human Vγ9/Vδ2 T cells in the defense against hematopoietic tumors that is distinct from NK cells.