Vδ2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and mount both immediate effector functions and memory responses after microbial infection. However, how Vδ2 T cells mediate different facets of a memory response remains unknown. Here, we show that the expression of CD45RA and CD27 antigens defines four subsets of human Vδ2 T cells with distinctive compartmentalization routes. Naive CD45RA+CD27+ and memory CD45RA−CD27+ cells express lymph node homing receptors, abound in lymph nodes, and lack immediate effector functions. Conversely, memory CD45RA−CD27− and terminally differentiated CD45RA+CD27− cells, which express receptors for homing to inflamed tissues, are poorly represented in the lymph nodes while abounding at sites of inflammation, and display immediate effector functions. These observations and additional in vitro experiments indicate a lineage differentiation pattern for human Vδ2 T cells that generates naive cells circulating in lymph nodes, effector/memory cells patrolling the blood, and terminally differentiated effector cells residing in inflamed tissues.
marrow complete remission (CR), and standard non-Hodgkin lymphoma (NHL) doses of rituximab in untreated CLL patients 4 cleared the bone marrow in only 9% of patients. We, therefore, would offer an alternative focus for future investigation with rituximab. Specifically, efforts should be focused on understanding potential factors such as stromal cell interaction that disrupt apoptosis, 5 CLL cell density, antibody penetration, and decreased access to complement and effector cells within the bone marrow that might prevent efficient clearance of tumor cells in the majority of patients. Such studies will facilitate development of alternative combination strategies to improve bone marrow responses with this promising combination therapy.
We investigated the interactions between human monocyte-derived dendritic cells (DCs) and Ag-activated circulating TCR-γδ-expressing lymphocytes (Vδ2). Coculture of immature DCs (iDCs) with peripheral blood Vδ2 T cells activated with either pyrophosphomonoesters (isopentenyl pyrophosphate; IPP) or aminobiphosphonates (pamidronate; PAM) led to a significant up-modulation of CD86 and MHC class I molecules and to the acquisition of functional features typical of activated DCs. DC activation induced by both IPP- and PAM-stimulated γδ T cells was mostly mediated by TNF-α and IFN-γ secreted by activated lymphocytes. However, the effect of PAM-activated γδ T cells, but not that of IPP-activated cells, required cell-to-cell contact. Reciprocally, activation of Vδ2 T cells by PAM, but not by IPP, was dependent on cell contact with iDCs. In fact, when PAM-stimulated DC-γδ T cell cocultures were separated by a semipermeable membrane or treated with blocking anti-CD86 Abs, induction of CD25 and CD69 as well as IFN-γ and TNF-α secretion by Vδ2 cells were strongly reduced. These results demonstrate for the first time a bidirectional activating interaction between iDCs and PAM-stimulated γδ T lymphocytes, thus suggesting a potential adjuvant role of this early cross-talk in the therapeutic activity of aminobiphosphonate drugs.
IntroductionHuman V␦2-T-cell receptor (TCR) ϩ lymphocytes constitute an unconventional lymphoid population. In striking contrast to "conventional" lymphocytes bearing the ␣ TCR, V␦2 T lymphocytes exhibit innate reactivity to major histocompatibility complex (MHC)-unrestricted microbial and tumoral nonpeptide antigens, which leads to proliferation, release of T-helper 1 (Th1) cytokines, and perforin-mediated killing. 1-3 Most circulating V␦2 cells are central memory and effector memory T cells, 4,5 reflecting selective activation by common environmental antigens, such as phosphorylated metabolites. Expression of cell-surface receptors for chemokines 6 and for MHC class I molecules 7,8 on a large fraction of V␦2 lymphocytes is also consistent with their memory phenotype.Circulating naive ␣ T cells use CD62L and CCR7 to bind high endothelial venules and to migrate to lymph nodes, respectively. 9 They also express the CD45RA isoform and the costimulatory receptor CD27, but after primary antigen encounter surface expression of these markers is gradually switched off. 10,11 On the other hand, experienced T cells comprise central memory (CD45RA Ϫ , CCR7 ϩ ), effector memory (CD45RA Ϫ , CCR7 Ϫ ), and CD45RA ϩ effector memory cells (CD45RA ϩ , CCR7 Ϫ ), which respectively produce increasing amounts of perforin. 9,12-15 Likewise, whereas most V␥9V␦2 T lymphocytes from cord blood are naive (CD45RA ϩ , CD27 ϩ ), most of their mature counterparts in adult blood from healthy individuals have lost the CD45RA receptor. 5 In addition, the effector functions of mature circulating V␦2 T cells comprise a potent cytolytic activity mediated by the release of perforin, 16 which is not produced by cord blood ␥␦ T cells. 17 CD45RA Ϫ CD27 ϩ cells are abundant in lymph nodes and lack immediate effector functions. Conversely, memory CD45RA Ϫ CD27 Ϫ and CD45RA ϩ CD27 Ϫ effector cells are poorly represented in lymph nodes but home in inflamed tissue and display immediate effector functions. 18 Recent evidence has revealed that natural killer (NK) cells can be divided in 2 distinct subpopulations with unique effector attributes based on expression of CD16. 19 This receptor binds immunoglobulin G (IgG) complexes to antigens and mediates phagocytosis, signal transduction, and antibody-dependent cellular cytotoxicity. Given the striking similarities between NK and ␥␦ cells, we investigated whether a similar distinction applied also for the latter population. Indeed, by multiparameter phenotyping of blood V␦2 T lymphocytes at the single-cell level using polychromatic flow cytometry, we define and characterize 2 different effector memory V␦2 T-cell subsets on the basis of CD16 expression. We describe their distinct phenotypes, patterns of stimulation, and functional responses. Finally, we suggest that these cells represent 2 different pathways of Materials and methods Cell preparation and culturePeripheral blood mononuclear cells (PBMCs) from healthy donors were isolated by Ficoll-Hypaque gradient centrifugation (Pharmacia, Uppsala, Sweden) and...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.