scholarly journals αβ/γδ T cell lineage outcome is regulated by intrathymic cell localization and environmental signals

2021 ◽  
Vol 7 (29) ◽  
pp. eabg3613
Author(s):  
Narges Aghaallaei ◽  
Advaita M. Dick ◽  
Erika Tsingos ◽  
Daigo Inoue ◽  
Eva Hasel ◽  
...  
Keyword(s):  
T Cells ◽  
High Frequency ◽  
Cell Lineage ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Environmental Signals ◽  
Cell Localization ◽  
Interleukin 7 ◽  
Αβ T Cells

αβ and γδ T cells are two distinct sublineages that develop in the vertebrate thymus. Thus far, their differentiation from a common progenitor is mostly understood to be regulated by intrinsic mechanisms. However, the proportion of αβ/γδ T cells varies in different vertebrate taxa. How this process is regulated in species that tend to produce a high frequency of γδ T cells is unstudied. Using an in vivo teleost model, the medaka, we report that progenitors first enter a thymic niche where their development into γδ T cells is favored. Translocation from this niche, mediated by chemokine receptor Ccr9b, is a prerequisite for their differentiation into αβ T cells. On the other hand, the thymic niche also generates opposing gradients of the cytokine interleukin-7 and chemokine Ccl25a, and, together, they influence the lineage outcome. We propose a previously unknown mechanism that determines the proportion of αβ/γδ lineages within species.

Abstract 87: Sterol-Mediated Regulation of γδ T Lymphocytes

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Hsin-Yuan Cheng ◽  
Catherine Hedrick
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lipid Content ◽  
Γδ T Cells ◽  
Brdu Incorporation ◽  
Γδ T Cell ◽  
High Fat ◽  
Αβ T Cells

Objective: gammadelta (γδ) T lymphocytes, which bridge innate and adaptive immunity, may be differentially regulated by cholesterol and play distinct roles from the conventional alphabeta (αβ) subset in the development of atherosclerosis. γδ T cells represent a small subset of total T cells (∼ 3-5% of CD3+ cells). These cells express unique γδ T cell receptors, and recognize lipid and peptide antigens without processing and presentation by MHC molecules. γδ T cells react much faster toward pathogen invasion than αβ T cells, and thus are considered one of the first lines of immune defense. Methods: αβ and γδ T lymphocytes from mice were evaluated for their lipid content, gene expression, proliferation, apoptosis, and activation. Results and conclusion: Nile Red staining revealed higher intracellular lipid content in γδ T cells, comparing to the αβ subset (1.3 folds of αβ, p<0.05; n=5). We therefore hypothesize that the basal higher sterol content elicits the turnover and activation of γδ T lymphocytes for rapid response. We found that genes involved in cholesterol esterification (ACAT1 and ACAT2) and efflux (ABCA1) are upregulated in γδ cells compared to conventional αβ T cells. PCSK9, which downregulates LDLR posttranslationally, is elevated in γδ T cells, suggesting cholesterol metabolism is differentially regulated in the two subsets. BrdU incorporation and annexin V staining revealed significantly higher proliferative (3.4 folds of αβ, p<0.001; n=8) and apoptotic (34.9 folds of αβ, p<0.001; n=6) rates of γδ T cells in vivo, suggesting a higher turnover rate of the γδ subset. Staining for ganglioside GM1 showed elevated lipid raft levels in γδ T cells (1.9 folds of αβ, p<0.001; n=8), implying enhanced TCR signaling and activation. Notably, the percentages of total (2.3 folds of αβ, p<0.01; n=3) and pro-inflammatory cytokine IL-17- producing (3.9 folds of αβ, p<0.01; n=4-5) γδ T cells increase in ApoE -/- mice fed a high cholesterol, high fat diet, implying a high sterol/high fat environment may promote γδ T cells activation in vivo. Taken together, our data suggest γδ T cells are more sensitive to cholesterol, and a high sterol environment may enhance γδ T cell turnover and activation in vivo.

γδ T cells for immune therapy of patients with lymphoid malignancies

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Martin Wilhelm ◽  
Volker Kunzmann ◽  
Susanne Eckstein ◽  
Peter Reimer ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Low Dose ◽  
Γδ T Cells ◽  
Low Grade ◽  
Treatment Schedule ◽  
Γδ T Cell

Abstract There is increasing evidence that γδ T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent γδ T cell stimulatory compounds that induce cytokine secretion (ie, interferon γ [IFN-γ]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of γδ T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of γδ T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 × 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, γδ T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of γδ T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of γδ T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of γδ T cells responded to treatment, indicating that γδ T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that γδ T-cell–mediated immunotherapy is feasible and can induce objective tumor responses. (Blood. 2003;102:200-206)

scholarly journals αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression

2021 ◽  
Vol 11 (9) ◽  
pp. 923
Author(s):  
Josephine G. M. Strijker ◽  
Ronja Pscheid ◽  
Esther Drent ◽  
Jessica J. F. van der Hoek ◽  
Bianca Koopmans ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcriptional Profiling ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Target Cells ◽  
Γδ T Cell ◽  
Mhc I ◽  
Organization Analysis ◽  
Αβ T Cells

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.

scholarly journals A new family of markers to characterize the human γδ T-cell lineage

2019 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Differentially Expressed Genes ◽  
Cell Lineage ◽  
Γδ T Cells ◽  
Differentially Expressed ◽  
Γδ T Cell ◽  
Differentiation Markers ◽  
Hematopoietic Stem ◽  
New Family

Prospective isolation of γδ T lymphocytes demands a comprehensive description of the molecules that distinguish T cells with γδ T-cell receptors (TCRs) (γδ T cells, or Tγδ) from those with αβTCRs (Tαβ). Here I describe some of the most differentially expressed genes in the γδ T cell when compared to the developmentally proximal but lineage-distinct Tαβ CD4+ and CD8+ lymphocytes. These genes encode cluster of differentiation markers, transcription factors, cell surface receptors and non-coding RNAs. As hematopoietic stem cells (HSCs) have been prospectively isolated based on the analysis of differentially expressed genes (1), any combination of these molecules may potentially be used to isolate Tγδ, perhaps even independent of the γδTCR. This description of the most striking identifying features of the Tγδ will be a resource for the isolation of a multi-potent common γδ T-cell progenitor.

scholarly journals An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer

2019 ◽  
Vol 11 (513) ◽  
pp. eaax9364 ◽  
Author(s):  
Yin Wu ◽  
Fernanda Kyle-Cezar ◽  
Richard T. Woolf ◽  
Cristina Naceur-Lombardelli ◽  
Julie Owen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Human Breast ◽  
Cell Compartment ◽  
Αβ T Cells

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells.

719 CD122-directed interleukin-2 complexes and αPD-L1 differentially require innate and adaptive immunity to treat local and metastatic bladder cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A761-A761
Author(s):  
Ryan Reyes ◽  
Yilun Deng ◽  
Deyi Zhang ◽  
Niannian Ji ◽  
Neelam Mukherjee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
San Antonio ◽  
Interleukin 2 ◽  
Γδ T Cells ◽  
List Type ◽  
Γδ T Cell

BackgroundαPD-L1 bladder cancer (BC) immunotherapy is effective in <30% of cases.1 To address the large αPD-L1-unresponsive subset of patients, we tested αIL-2/IL-2 complexes (IL-2c) that block IL-2 from binding high-affinity IL-2Rα (CD25) for preferential IL-2Rβ (CD122) binding.2 Immunosuppressive regulatory T cells capture IL-2 by CD25 whereas antitumor CD8+ T, γδ T, and NK cells use CD122. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe used PD-L1+ mouse BC cell lines MB49 and MBT-2, for orthotopic, intravesical (i.e., in bladder) and intravenous challenge studies of local versus lung metastatic BC.ResultsαPD-L1 or IL-2c alone reduced tumor burden and extended survival in local MB49 and MBT-2. Using in vivo cell depletions, we found that γδ T cells and NK cells, but strikingly not CD8+ T cells, were necessary for IL-2c efficacy in bladder. We confirmed γδ T cell requirements for IL-2c, but not αPD-L1 efficacy in γδ T cell-null TCRδKO mice. TCRβKO conventional T cell-null mice exhibited IL-2c, but not αPD-L1 responsiveness for orthotopic BC treatment. Neither agent alone treated lung metastatic MB49 or MBT-2 but the drug combination improved survival in both tumor models. Combination treatment effects in lungs were distinct from bladder, requiring CD8+ T and NK cells, but not γδ T cells.ConclusionsBC immunotherapy effects differ by anatomic compartment and use distinct mechanisms to treat primary and metastatic BC. CD122-directed IL-2 is a promising BC immunotherapy strategy, and IL-2c is a candidate mediator through innate immune effects. αPD-L1 could improve IL-2c efficacy by engagement of adaptive immune responses including to improve metastatic disease treatment efficacy.Ethics ApprovalAll procedures involving animals in this study were approved by the UT Health San Antonio Institutional Animal Care and Use Committee (IACUC) and conducted in accordance with UT Health San Antonio Department of Laboratory Animal Resources standards.ReferencesShah AY, Gao J, Siefker-Radtke AO. Five new therapies or just one new treatment? A critical look at immune checkpoint inhibition in urothelial cancer: Future Medicine, 2017.Arenas-Ramirez N, Zou C, Popp S, et al. Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Science translational medicine 2016;8(367):367ra166-367ra166.

Recovery Of Gamma/Delta+ T Cells After Transplantation With Alpha-Beta+/CD19+ Lymphocyte Depleted Hematopoietic Stem Cells From HLA-Haploidentical Donors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3245-3245
Author(s):  
Irma Airoldi ◽  
Ignazia Prigione ◽  
Alice Bertaina ◽  
Claudia Cocco ◽  
Daria Pagliara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Zoledronic Acid ◽  
Γδ T Cells ◽  
Leukemia Cells ◽  
Γδ T Cell ◽  
Hematopoietic Stem ◽  
Functional Studies ◽  
Αβ T Cells ◽  
Over Time

Abstract HLA-haploidentical hematopoietic stem cell transplantation (HSCT) using CD34+ selected cells is a widely used procedure, which, however, is complicated by delayed immune reconstitution. We recently developed a new method of graft manipulation based on the physical removal of αβ+ T cells and CD19+ B cells, which permits to leave mature natural killer (NK) cells and γδ+ T cells in the graft. These cells can exert a graft-versus-leukemia (GvL) effect and reduce the risk of infection. In particular, unconventional γδ T cells play a critical role in both innate and adaptive immunity and exert HLA-unrestricted cytotoxicity against both solid and hematological tumors, thus potentially acting as beneficial effector cells in transplanted patients. Moreover, such grafts may limit the risk of graft-versus-host disease and prevent EBV-related lymphoproliferative disease. We performed phenotypic and functional studies on γδ T cells collected from 20 pediatric patients (pts, 13 males, 7 females, median age 10 years, range 6 months to 16 years) that received this type of allograft. Eighteen pts had acute leukemia and 2 non-malignant disorders. Ex vivo assays of peripheral blood γδ T cell phenotype and function were performed weekly until Hospital discharge and monthly until 6 months after HSCT. Phenotype of γδ T cells was analysed by flow cytometry. Analyses were performed on mononuclear cells labelled with mAb panels (CD3, CD45, pan-γδ, anti-Vδ1, -Vδ2, -Vγ9, CD45RO, CD45RA, CD27, CD16, CD56) allowing the identification of the main γδ+ T cell subsets, including Vδ1+ and Vδ2+ cells, naïve, central memory (CM), effector memory (EM) and terminally differentiated (TD) γδ T cells. Functional studies were performed using γδ T cells shortly after collection from pts, as well as after in vitro expansion with zoledronic acid and IL-2 for 10 days. Cytotoxic activity of γδ T cells was tested against primary leukemia cells, through CD107a degranulation assay and/or standard 51Cr-release assay. In the first 4 weeks after HSCT, T cells were consistently of the γδ subset (>90% of CD45+CD3+ cells); by contrast, αβ+ T cells gradually increased over time. In approximately half of the pts, the percentage of αβ T cells exceeded that of γδ T cells already starting from 30 days after HSCT. γδ T cells consisted of Vδ2+Vγ9+ and Vδ1+Vγ9+/- cells, and marginally of the Vδ1-Vδ2-Vγ9- population. Detailed phenotypic characterization of Vδ1+ and Vδ2+ γδ T cells revealed that, at day +20 after HSCT, 44% of Vδ1+ cells were CM (identified as CD45RO+CD27+ cells), 26% naïve (CD45RO-CD27+), 21.4% TD (CD45RO-CD27-) and 6.1% EM (CD45RO+CD27-). Similarly, 55.4% of Vδ2+ γδ T lymphocytes were CM, 9.8% naïve, 11.4% TD and 23.1% EM. The proportion of the different Vδ2+ γδ T cell subset did not change significantly over time, especially when comparing that present at day +20 after HSCT (time point, TP1) with that measured 30 days after the attainment of a 1:1 ratio of αβ-to- γδ T cells (TP2) (Figure 1, left panel). By contrast, by comparing TP1 and TP2, we found that Vδ1+ CM γδ T cells decreased and EM cells increased over time, while naïve or TD Vδ1+ γδ T cells did not change (Figure 1, right panel). In transplanted pts experiencing cytomegalovirus (CMV) reactivation, γδ T cells mostly consisted of Vδ1+ cells (mean 59.8% of γδ T cells), among which 49% were TD, 22.7% EM, 18.9% CM and 10.1% naïve. Noteworthy, in transplanted pts who did not have CMV reactivation, the main γδ T cells showed a Vδ2+ phenotype. Functional studies revealed that pt-derived γδ T cells consistently expanded in vitro after exposure to zoledronic acid and IL-2, the resulting Vγ9Vδ2 population expressing mainly an EM phenotype. These Vγ9Vδ2 cells exerted cytotoxic activities against primary allogeneic leukemia cells, especially when leukemia cells were pre-treated with zoledronic acid (Figure 2). More importantly, both Vδ1+ and Vδ2+ γδ T cells obtained from transplanted pts showed cytotoxic activity against primary leukemia cells, as assessed by CD107a degranulation assay. In conclusion, we provide the first phenotypic and functional characterization of γδ T cells, analyzed over time in children transplanted with grafts depleted of αβ+ T cells and of B lymphocytes. Our results support the concept that γδ T cells are important effector cells, which can be expanded and activated after exposure to bisphosphonates and IL-2 with the aim of improving their killing capacity against leukemia cells. Disclosures: No relevant conflicts of interest to declare.

Quantitative and Functional Alterations of the Gamma Delta T-Cell Subset within Follicular Lymphoma Microenvironment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2601-2601
Author(s):  
Sophie de Guibert ◽  
Jean-Baptiste Thibert ◽  
Céline Bonnaventure ◽  
Patricia Ame-Thomas ◽  
Céline Pangault ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Peripheral Blood ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Ifn Γ ◽  
Nonpeptide Antigens

Abstract T cells carrying a γδ TCR account for less than 5% of CD3pos T cells in healthy individuals but are key effectors of innate immunity through the recognition of some unprocessed nonpeptide antigens of both self and foreign origin. Whereas the Vδ2 subpopulation represents more than 70% of peripheral blood γδ T cells, the Vδ1 subset is mainly located in the mucosal tissue. Increasing evidence suggest that γδ T cells have potent antitumor activity and are implicated in the defense against some haematological and epithelial malignancies. Moreover, Vδ2 T cells constitute an attractive immunotherapy strategy since they could be expanded and activated both in vivo and in vitro using synthetic phosphoantigens and aminobiphosphonates. Such strategies are currently tested in preliminary clinical trials, notably in follicular lymphoma (FL). However, an exhaustive phenotypic and functional characterisation of γδ T cells in this disease, including tumor infiltration, is still lacking. We first explored the composition of FL microenvironment using a multicolour flow cytometry analysis. We observed a significant decrease in the percentage of myeloid (LinnegCD11cposHLADRpos) and plasmacytoid (LinnegCD123posHLADRpos) dendritic cells (P = .0011 and P &lt; .0001, respectively) in FL compared to normal secondary lymphoid organs. In addition, among CD3pos T cells, the proportion of follicular helper T cells (CD4posCXCR5posICOShi) was increased (P = .001) whereas regulatory T-cell (CD4posCD25posfoxp3pos) frequency was not altered. When considering the γδ T-cell compartment, we first highlighted a reduction of the Vδ2 subset in normal tonsils (Vδ2 = 23.48 ± 0.15% of γδ T cells, n = 11) when compared with peripheral blood. Remaining non-δ2 γδT cells were predominantly δ1 T cells. More importantly, infiltrating γδ T cells were significantly decreased in lymph node biopsies from FL patients (mean = 0.48 ± 0.4% of CD3pos T cells; n = 27) when compared both to normal tonsils (mean = 2.49 ± 1.6% of CD3pos T cells; n = 33) (P &lt; .0001) and reactive lymph nodes (mean = 2.64 ± 2.6% of CD3pos T cells; n = 9) (P = .0009). This reduction affected both the Vδ1 and Vδ2 T-cell subsets. The functionality of γδ T cells was then assessed by the measurement of cell expansion and production of IFN-γ upon stimulation with the isopentenyl pyrophosphate (IPP) phosphoantigen. Amplification rate in vitro reached 14.6 ± 4.6 fold in tonsils (n = 10) but only 4.36 ± 1.9 fold in FL samples (n = 7) (P &lt; .002) after 5 days of culture in the presence of IPP + IL-2 + IL-15. When focusing on the δ2 subset, this difference was further increased with a 40-fold amplification in tonsil and a 3-fold amplification in FL samples (P = .0004). Evaluation of IFN-γ production using ELISPOT assay revealed a high heterogeneity among tumor samples since 1 to 40% of δ2 T cells were able to respond to IPP stimulation (n = 7). Preliminary data argued for an association between the quantity and the functionality of γδ T cells in FL tumors. In conclusion, we reported an alteration of γδ T cell frequency and functionality within FL tumor niche. The next purpose will be to correlate these in vitro defects with in vivo clinical responses to immunotherapy strategies targeting γδ T cells.

scholarly journals The Unknown Unknowns: Recovering Gamma-Delta T Cells for Control of Human Immunodeficiency Virus (HIV)

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1455
Author(s):  
Shivkumar Biradar ◽  
Michael T. Lotze ◽  
Robbie B. Mailliard
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
T Cell Biology ◽  
Immunodeficiency Virus

Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential.

scholarly journals Mechanisms underlying γδ T-cell subset perturbations in SIV-infected Asian rhesus macaques

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4148-4157 ◽  
Author(s):  
Levelle D. Harris ◽  
Nichole R. Klatt ◽  
Carol Vinton ◽  
Judith A. Briant ◽  
Brian Tabb ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rhesus Macaques ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Microbial Translocation ◽  
Therapeutic Interventions ◽  
Γδ T Cell ◽  
Gastrointestinal Mucosa

Abstract T cells that express the γδ T-cell receptor, which recognize microbial or stress-induced antigens, represent a minority of blood T cells but constitute a major proportion of intraepithelial lymphocytes in the gastrointestinal mucosa. As microbial products have been shown to translocate from the gastrointestinal tract into circulation in chronically HIV/Simian immunodeficiency virus (SIV)–infected individuals, we conducted a study of Vδ1 and Vδ2 T-cell frequency, phenotype, and function in blood, spleen, lymph nodes, gastrointestinal mucosa, and bronchoalveolar lavage of uninfected and chronically SIVsmE543-infected rhesus macaques (RMs). We found: (1) SIV-associated inversion of Vδ1/Vδ2 T cells occurs in blood and in several tissues; (2) γδ T cells are not infected by SIV in vivo; (3) the Vδ1/Vδ2 inversion involves expansion of Vδ1 T cells; (4) expanded Vδ1 T cells are phenotypically and functionally different from Vδ1 T cells from uninfected RMs; and (5) the stimulus underlying expansion of Vδ1 T cells appears to be microbial translocation. These data highlight the importance of microbial translocation–induced immune activation in chronically infected individuals and provide new insights into an immune dysregulation phenomenon that is a hallmark of HIV/SIV infection. These findings may lead to novel therapeutic interventions that improve the immune responses against microbial antigens, and thus, decrease microbial translocation–induced im-mune activation.

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