Cheap and Commonplace: Making the Case for BCG and γδ T Cells in COVID-19

Antigen-specific vaccines developed for the COVID-19 pandemic demonstrate a remarkable achievement and are currently being used in high income countries with much success. However, new SARS-CoV-2 variants are threatening this success via mutations that lessen the efficacy of antigen-specific antibodies. One simple approach to assisting with this issue is focusing on strategies that build on the non-specific protection afforded by the innate immune response. The BCG vaccine has been shown to provide broad protection beyond tuberculosis disease, including against respiratory viruses, and ongoing studies are investigating its efficacy as a tool against SARS-CoV-2. Gamma delta (γδ) T cells, particularly the Vδ2 subtype, undergo rapid expansion after BCG vaccination due to MHC-independent mechanisms. Consequently, γδ T cells can produce diverse defenses against virally infected cells, including direct cytotoxicity, death receptor ligands, and pro-inflammatory cytokines. They can also assist in stimulating the adaptive immune system. BCG is affordable, commonplace and non-specific, and therefore could be a useful tool to initiate innate protection against new SARS-CoV-2 variants. However, considerations must also be made to BCG vaccine supply and the prioritization of countries where it is most needed to combat tuberculosis first and foremost.

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CD56+ human blood dendritic cells effectively promote TH1-type γδ T-cell responses

Blood ◽

10.1182/blood-2009-06-227256 ◽

2009 ◽

Vol 114 (20) ◽

pp. 4422-4431 ◽

Cited By ~ 33

Author(s):

Georg Gruenbacher ◽

Hubert Gander ◽

Andrea Rahm ◽

Walter Nussbaumer ◽

Nikolaus Romani ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Human Blood ◽

Γδ T Cells ◽

Rapid Expansion ◽

Γδ T Cell ◽

Hla Dr ◽

Tnf Α ◽

Ifn Γ

Abstract CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant γδ T cells with zoledronate and interleukin-2 (IL-2) resulted in the rapid expansion of γδ T cells as well as in IFN-γ, TNF-α, and IL-1β but not in IL-4, IL-10, or IL-17 production. IFN-γ, TNF-α, and IL-1β production were almost completely abolished by depleting CD14+ cells from the CD56+ subset before stimulation. Likewise, depletion of CD14+ cells dramatically impaired γδ T-cell expansion. IFN-γ production could also be blocked by neutralizing the effects of endogenous IL-1β and TNF-α. Conversely, addition of recombinant IL-1β, TNF-α, or both further enhanced IFN-γ production and strongly up-regulated IL-6 production. Our data indicate that CD56+ DCs from human blood are capable of stimulating CD56+ γδ T cells, which may be harnessed for immunotherapy.

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Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1914667117 ◽

2020 ◽

Vol 117 (23) ◽

pp. 12961-12968 ◽

Cited By ~ 3

Author(s):

M. Zeeshan Chaudhry ◽

Rosaely Casalegno-Garduno ◽

Katarzyna M. Sitnik ◽

Bahram Kasmapour ◽

Ann-Kathrin Pulm ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

Cd8 T Cells ◽

Cell Function ◽

Death Receptor ◽

Cd8 T Cell ◽

Cytotoxic T Cell ◽

Caspase 8 ◽

Infected Cells

Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.

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The dynamics of granuloma formation in experimental visceral leishmaniasis.

Journal of Experimental Medicine ◽

10.1084/jem.167.6.1927 ◽

1988 ◽

Vol 167 (6) ◽

pp. 1927-1937 ◽

Cited By ~ 91

Author(s):

M J McElrath ◽

H W Murray ◽

Z A Cohn

Keyword(s):

T Cells ◽

Specific Antigen ◽

Cell Types ◽

Host Cells ◽

Cytotoxic Potential ◽

Sequence Of Events ◽

Direct Cytotoxicity ◽

Infected Cells ◽

Parasite Replication ◽

Hepatic Granulomas

We have examined the temporal sequence of events leading to the formation of hepatic granulomas after the intravenous injection of L. donovani amastigotes into BALB/c mice. Parasite ingestion by permissive Kupffer cells (KC) occurred promptly, and local KC aggregations were the foci about which granulomas were subsequently formed. Infected KC were recognized by the uptake of colloidal carbon and the expression of the macrophage-specific antigen recognized by F4/80 mAb. Peroxidase-positive granulocytes migrated rapidly and were followed by monocytes and L3T4+ T cells that enclosed the infected KC. Thereafter, Ly-2+ T cells were prominent members of the granulomatous lymphoid population. Parasites multiplied until 4 wk, and then a prompt reduction in infected cells occurred. This was associated with a sharp decline in the L3T4+ T cells of the granulomas and the maintenance of the Ly-2+ subset. In comparison, athymic nu/nu mice developed smaller, more slowly appearing granulomas that contained granulocytes and monocytes and exhibited progressive parasite replication. Upon rechallenge, the entire process was completed in 2 wk, and infected KC in the euthymic mice were never observed. We hypothesize that the effectiveness of the granulomatous response requires the destruction of parasitized host cells (KC), in a lymphokine rich environment. We further suggest that the Ly-2+ T cell serves as an important effector cell in this process, either by direct cytotoxicity or by supporting the cytotoxic potential of other cell types in the granuloma.

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Differential Activation of V γ4V δ1 and V γ9V δ2 Cord Blood Derived Gamma Delta T Cells upon Exposure to EBV-Lcl and K562 Cells

Blood ◽

10.1182/blood-2021-152151 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2790-2790

Author(s):

Jeremy Wee Kiat Ng ◽

Joey Lai ◽

Tony Kiat Hon Lim ◽

William YK Hwang ◽

Shang Li ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cord Blood ◽

Single Cell ◽

Γδ T Cells ◽

Rapid Expansion ◽

Leukemia Cell Line ◽

Γδ T Cell ◽

Gamma Delta

Abstract Gamma-delta (γδ) T cells have emerged as a promising candidate for adoptive cellular immunotherapy. To harness and maximize the anti-leukemia properties of these cells, we sort to comprehensively profile the transcriptomic signatures and immune repertoire of in vitro expanded γδ T cell products. Given the reported diverse TCR γδ repertoire and naïve nature of γδ T cells found in human cord blood (CB γδ), we serially track the molecular and cellular changes in these cells upon activation in expansion cultures. Based on the established viral reactivities of γδ T cell as well as prior studies showing their cross reactivities against leukemia and cancer cells, we had previously shown that stimulating CB γδ with an irradiated EBV-LCL feeder cell-based rapid expansion protocol (REP) is capable of generating cell products with potent and specific cytotoxicity against human AML cells. In the present study, using single cell RNA sequencing (scRNA-seq) coupled with single cell TCR γδ repertoire analysis, we compared the transcription signatures between our REP expanded γδ T cell (REP γδ) and non-manipulated γδ T cells reported in literatures, showing the progressive acquisition of an adult PB derived γδ T cell (PB γδ)-like cell states. Time course analysis demonstrated complex T cell activation and maturation trajectories correlating with variable level of clonal induction throughout the course of in vitro expansion. At the end of expansion, the harvested REP γδ are predominantly of the V γ4V δ1 subtype. Nevertheless, upon exposing REP γδ to target leukemia cell line K562, outgrowth of other non-V γ4V δ1 as well as the semi-invariant V γ9V δ2 cells were observed. Taken together, our data shows that as CB γδ expand and differentiate in culture, they adopt an adult PB γδ-like program. More importantly, our data highlights the rich clonal composition of in vitro expanded CB γδ, with different clonotypes being variably activated upon exposure to different stimuli. Such characteristics can potentially overcome the challenges of cancer heterogeneity and cell persistence, with the potential of improving outcomes in cell immunotherapy. Disclosures No relevant conflicts of interest to declare.

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Donor Vδ1+ γδ T cells expand after allogeneic hematopoietic stem cell transplantation and show reactivity against CMV-infected cells but not against progressing B-CLL

Experimental Hematology and Oncology ◽

10.1186/2162-3619-2-14 ◽

2013 ◽

Vol 2 (1) ◽

Cited By ~ 7

Author(s):

Immo Prinz ◽

Kristina Thamm ◽

Matthias Port ◽

Eva M Weissinger ◽

Michael Stadler ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Γδ T Cells ◽

Hematopoietic Stem ◽

Infected Cells

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Shared reactivity of Vδ2neg γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells

Journal of Experimental Medicine ◽

10.1084/jem.20041851 ◽

2005 ◽

Vol 201 (10) ◽

pp. 1567-1578 ◽

Cited By ~ 159

Author(s):

Franck Halary ◽

Vincent Pitard ◽

Dorota Dlubek ◽

Roman Krzysiek ◽

Henri de la Salle ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Γδ T Cells ◽

Γδ T Cell ◽

Kidney Transplant Recipients ◽

T Cell Clones ◽

Cell Clones ◽

Infected Cells

Long-lasting expansion of Vδ2neg γδ T cells is a hallmark of cytomegalovirus (CMV) infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, we generated γδ T cell clones from several transplanted patients. Numerous patient Vδ1+, Vδ3+, and Vδ5+ γδ T cell clones expressing diverse Vγ chains, but not control Vγ9Vδ2+ T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of tumor necrosis factor-α. Vδ2neg γδ T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required T cell receptor engagement, but did not involve major histocompatibility complex class I molecules or NKG2D. Vδ2neg γδ T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific Vδ2neg γδ T lymphocytes were found among patients' γδ T cells. In conclusion, Vδ2neg γδ T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from Vγ9Vδ2+ T cells.

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Gamma Delta T Cells and Their Involvement in COVID-19 Virus Infections

Frontiers in Immunology ◽

10.3389/fimmu.2021.741218 ◽

2021 ◽

Vol 12 ◽

Author(s):

Georg von Massow ◽

Steve Oh ◽

Alan Lam ◽

Kenth Gustafsson

Keyword(s):

T Cells ◽

Viral Infections ◽

Cell Subset ◽

Γδ T Cells ◽

Common Symptom ◽

Virus Infections ◽

Infected Cells ◽

The Relationship

The global outbreak of the SARS-Cov-2 virus in 2020 has killed millions of people worldwide and forced large parts of the world into lockdowns. While multiple vaccine programs are starting to immunize the global population, there is no direct cure for COVID-19, the disease caused by the SARS-Cov-2 infection. A common symptom in patients is a decrease in T cells, called lymphopenia. It is as of yet unclear what the exact role of T cells are in the immune response to COVID-19. The research so far has mainly focused on the involvement of classical αβ T cells. However, another subset of T cells called γδ T cells could have an important role to play. As part of the innate immune system, γδ T cells respond to inflammation and stressed or infected cells. The γδ T cell subset appears to be particularly affected by lymphopenia in COVID-19 patients and commonly express activation and exhaustion markers. Particularly in children, this subset of T cells seems to be most affected. This is interesting and relevant because γδ T cells are more prominent and active in early life. Their specific involvement in this group of patients could indicate a significant role for γδ T cells in this disease. Furthermore, they seem to be involved in other viral infections and were able to kill SARS infected cells in vitro. γδ T cells can take up, process and present antigens from microbes and human cells. As e.g. tumour-associated antigens are presented by MHC on γδ T cells to classical T-cells, we argue here that it stands to reason that also viral antigens, such as SARS-Cov-2-derived peptides, can be presented in the same way. γδ T cells are already used for medical purposes in oncology and have potential in cancer therapy. As γδ T cells are not necessarily able to distinguish between a transformed and a virally infected cell it could therefore be of great interest to investigate further the relationship between COVID-19 and γδ T cells.

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Abstract 025: Lacking of Gamma Delta T Cells Exaggerate Cardiac Dysfunction in Angiotensin II-induced Hypertension in Balb/cByJ Mice

Hypertension ◽

10.1161/hyp.70.suppl_1.025 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Tang-Dong Liao ◽

Jiang Xu ◽

Oscar A Carretero

Keyword(s):

T Cells ◽

Cardiac Function ◽

Γδ T Cells ◽

Adaptive Immune System ◽

Cell Receptor ◽

Organ Damage ◽

Ang Ii ◽

Gamma Delta ◽

Induced Hypertension ◽

Eccentric Hypertrophy

Gamma Delta T lymphocytes are important innate immune component which express γδ T cell receptor (TCR). These cells are capable of spontaneous secretion of IL-17 and IFN gamma proinflammatory cytokines. Recently, new evidence suggests that the innate and adaptive immune system is involved in the hypertension and end-organ damage. We tested the hypothesis whether deficiency in γδ TCR has a beneficial effect on cardiac function in Angiotension II (Ang II)-induced hypertension. Male Balb/cByj wild-type (WT) and Tcrγδ knockout (Tcrγδ-/-) mice were infused with vehicle or Ang II at dosage of 400ng/kg/min for 4 weeks. Our results showed Systolic blood pressure (SBP) was increased significantly after 1 week of Ang II infusion, and the increase was sustained 4 weeks in WT mice, however in Tcrγδ-/- mice, SBP dropped significantly at 4 weeks compared to WT (table1). Echocardiography data showed that ejection fraction (EF) and shortening fraction (SF) were decreased significantly after Ang II infusion; these effects were exacerbated in Tcrγδ-/- mice given Ang II. Also both mass and chamber dimension increased greater in Tcrγδ-/- mice given Ang II compared to WT (table1). The results indicated Tcrγδ-/- mice given Ang II develop eccentric hypertrophy. We conclude that lacking of γδ T cells has a detrimental effect on cardiac function in Ang II-induced hypertension in Balb/cByJ mice. table1:

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Antibody-dependent anti-cytomegalovirus activity of human γδ T cells expressing CD16 (FcγRIIIa)

Blood ◽

10.1182/blood-2011-06-363655 ◽

2012 ◽

Vol 119 (6) ◽

pp. 1418-1427 ◽

Cited By ~ 69

Author(s):

Lionel Couzi ◽

Vincent Pitard ◽

Xavier Sicard ◽

Isabelle Garrigue ◽

Omar Hawchar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hcmv Infection ◽

Γδ T Cells ◽

Cell Receptor ◽

T Cell Response ◽

Transplant Recipients ◽

Antiviral Function ◽

Infected Cells

Abstract Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in transplant recipients. Long-term protective immunity against HCMV requires both sustained specific T-cell response and neutralizing IgG production, but the interplay between these effector arms remains poorly defined. We previously demonstrated that γδ T cells play a substantial role as anti-HCMV T-cell effectors. The observation that CD16 (FcγRIIIA) was specifically expressed by the majority of HCMV-induced γδ T cells prompted us to investigate their cooperation with anti-HCMV IgG. We found that CD16 could stimulate γδ T cells independently of T-cell receptor (TCR) engagement and provide them with an intrinsic antibody-dependent cell-mediated cytotoxic (ADCC) potential. Although CD16+γδ T cells did not mediate ADCC against HCMV-infected cells, in accordance with the low level of anti-HCMV IgGs recognizing infected cells, they produced IFNγ when incubated with IgG-opsonized virions. This CD16-induced IFNγ production was greatly enhanced by IL12 and IFNα, 2 cytokines produced during HCMV infection, and conferred to γδ T cells the ability to inhibit HCMV multiplication in vitro. Taken together, these data identify a new antiviral function for γδ T cells through cooperation with anti-HCMV IgG that could contribute to surveillance of HCMV reactivation in transplant recipients.

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