Faculty Opinions recommendation of γδ-T cells promote IFN-γ-dependent Plasmodium pathogenesis upon liver-stage infection.

Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.

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Cryopreservation of Whole Tumor Biopsies from Rectal Cancer Patients Enable Phenotypic and In Vitro Functional Evaluation of Tumor-Infiltrating T Cells

Cancers ◽

10.3390/cancers13102428 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2428

Author(s):

Frank Liang ◽

Azar Rezapour ◽

Peter Falk ◽

Eva Angenete ◽

Ulf Yrlid

Keyword(s):

Rectal Cancer ◽

T Cells ◽

Γδ T Cells ◽

T Cell Subsets ◽

Functional Evaluation ◽

Mait Cells ◽

Ifn Γ ◽

Tumor Biopsies

TILs comprise functionally distinct conventional and unconventional T cell subsets and their role in responses to CRC treatments is poorly understood. We explored recovery of viable TILs from cryopreserved tumor biopsies of (chemo)-radiated patients with rectal cancer to establish a platform for retrospective TIL analyses of frozen tumors from pre-selected study cohorts. Frequencies of TIL subsets and their capacity to mount IFN-γ responses in cell suspensions of fresh vs. cryopreserved portions of the same tumor biopsies were determined for platform validation. The percentages and proportions of CD4+ TILs and CD8+ cytotoxic T lymphocytes (CTLs) among total TILs were not affected by cryopreservation. While recovery of unconventional γδ T cells and mucosal-associated invariant T cells (MAIT cells) was stable after cryopreservation, the regulatory T cells (Tregs) were reduced, but in sufficient yields for quantification. IFN-γ production by in vitro-stimulated CD4+ TILs, CTLs, γδ T cells, and MAIT cells were proportionally similar in fresh and cryopreserved tumor portions, albeit the latter displayed lower levels. Thus, the proposed platform intended for TIL analyses on cryopreserved tumor biobank biopsies holds promises for studies linking the quantity and quality of TIL subsets with specific clinical outcome after CRC treatment.

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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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Bovine Immune Response to Vaccination and Infection with Leptospira borgpetersenii Serovar Hardjo

mSphere ◽

10.1128/msphere.00988-20 ◽

2021 ◽

Vol 6 (2) ◽

Author(s):

Jennifer H. Wilson-Welder ◽

David P. Alt ◽

Jarlath E. Nally ◽

Steven C. Olsen

Keyword(s):

Immune Response ◽

T Cells ◽

Lymph Nodes ◽

Γδ T Cells ◽

Regional Lymph Nodes ◽

Content Type ◽

Oil Emulsion ◽

Leptospira Borgpetersenii ◽

Ifn Γ ◽

Experimental Challenge

ABSTRACT This study examined the humoral and cellular response of cattle vaccinated with two commercial leptospiral vaccines, Leptavoid and Spirovac, and a novel bacterin vaccine using Seppic Montanide oil emulsion adjuvant. Vaccination was followed by experimental challenge. All vaccinated cattle were protected from colonization of the kidney and shedding of Leptospira in urine, as detected by culture and immunofluorescence assay. Agglutinating antibody titers were detected in vaccinated cattle at 4 weeks following vaccination, with small anamnestic response detected following experimental challenge. Only animals vaccinated with the oil emulsion-adjuvanted bacterin produced significant IgG2 titers following vaccination, and nonvaccinated animals produced serum IgA titers after experimental challenge. CD4+ and γδ T cells from vaccinated cattle proliferated when cultured with antigen ex vivo. Cellular responses included a marked proliferation of γδ T cells immediately following experimental challenge in vaccinated cattle and release of gamma interferon (IFN-γ), interleukin 17a (IL-17a), and IL-12p40 from stimulated cells. Proliferative and cytokine responses were found not just in peripheral mononuclear cells but also in lymphocytes isolated from renal lymph nodes at 10 weeks following experimental challenge. Overall, effects of leptospirosis vaccination and infection were subtle, resulting in only modest activation of CD4+ and γδ T cells. The use of Seppic Montanide oil emulsion adjuvants may shorten the initiation of response to vaccination, which could be useful during outbreaks or in areas where leptospirosis is endemic. IMPORTANCE Leptospirosis is an underdiagnosed, underreported zoonotic disease of which domestic livestock can be carriers. As a reservoir host for Leptospira borgpetersenii serovar Hardjo, cattle may present with reproductive issues, including abortion, birth of weak or infected calves, or failure to breed. Despite years of study and the availability of commercial vaccines, detailed analysis of the bovine immune response to vaccination and Leptospira challenge is lacking. This study evaluated immunologic responses to two efficacious commercial vaccines and a novel bacterin vaccine using an adjuvant chosen for enhanced cellular immune responses. Antigen-specific responsive CD4 and γδ T cells were detected following vaccination and were associated with release of inflammatory cytokines IFN-γ and IL-17a after stimulation. CD4 and γδ cells increased in the first week after infection and, combined with serum antibody, may play a role in clearance of bacteria from the blood and resident tissues. Additionally, these antigen-reactive T cells were found in the regional lymph nodes following infection, indicating that memory responses may not be circulating but are still present in regional lymph nodes. The information gained in this study expands knowledge of bovine immune response to leptospirosis vaccines and infection. The use of oil emulsion adjuvants may enhance early immune responses to leptospiral bacterins, which could be useful in outbreaks or situations where leptospirosis is endemic.

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Pulmonary Interleukin-17-Positive Lymphocytes Increase during Pneumocystis murina Infection but Are Not Required for Clearance of Pneumocystis

Infection and Immunity ◽

10.1128/iai.00434-16 ◽

2017 ◽

Vol 85 (7) ◽

Cited By ~ 5

Author(s):

Chiara Ripamonti ◽

Lisa R. Bishop ◽

Joseph A. Kovacs

Keyword(s):

T Cells ◽

Fungal Infections ◽

Intracellular Cytokine Staining ◽

Γδ T Cells ◽

Interleukin 17 ◽

Content Type ◽

Immunosuppressed Patients ◽

Ifn Γ ◽

Immunocompetent Mice ◽

Deficient Mice

ABSTRACT Pneumocystis remains an important pathogen of immunosuppressed patients, causing a potentially life-threatening pneumonia. Despite its medical importance, the immune responses required to control infection, including the role of interleukin-17 (IL-17), which is important in controlling other fungal infections, have not been clearly defined. Using flow cytometry and intracellular cytokine staining after stimulation with phorbol myristate acetate and ionomycin, we examined gamma interferon (IFN-γ), IL-4, IL-5, and IL-17 production by lung lymphocytes in immunocompetent C57BL/6 mice over time following infection with Pneumocystis murina. We also examined the clearance of Pneumocystis infection in IL-17A-deficient mice. The production of both IFN-γ and IL-17 by pulmonary lymphocytes increased during infection, with maximum production at approximately days 35 to 40, coinciding with peak Pneumocystis levels in the lungs, while minimal changes were seen in IL-4- and IL-5-positive cells. The proportion of cells producing IFN-γ was consistently higher than for cells producing IL-17, with peak levels of ∼25 to 30% of CD3+ T cells for the former compared to ∼15% for the latter. Both CD4+ T cells and γδ T cells produced IL-17. Administration of anti-IFN-γ antibody led to a decrease in IFN-γ-positive cells, and an increase in IL-5-positive cells, but did not impact clearance of Pneumocystis infection. Despite the increases in IL-17 production during infection, IL-17A-deficient mice cleared Pneumocystis infection with kinetics similar to C57BL/6 mice. Thus, while IL-17 production in the lungs is increased during Pneumocystis infection in immunocompetent mice, IL-17A is not required for control of Pneumocystis infection.

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The Dissection of CD8 T Cells During Liver-Stage Infection

Current Topics in Microbiology and Immunology - Immunology and Immunopathogenesis of Malaria ◽

10.1007/3-540-29967-x_1 ◽

2005 ◽

pp. 1-24 ◽

Cited By ~ 15

Author(s):

U. Krzych ◽

R. J. Schwenk

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Liver Stage ◽

Stage Infection

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γδ T cells provide the early source of IFN-γ to aggravate lesions in spinal cord injury

Journal of Experimental Medicine ◽

10.1084/jem.20170686 ◽

2017 ◽

Vol 215 (2) ◽

pp. 521-535 ◽

Cited By ~ 27

Author(s):

Guodong Sun ◽

Shuxian Yang ◽

Guangchao Cao ◽

Qianghua Wang ◽

Jianlei Hao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

T Cells ◽

Functional Recovery ◽

Γδ T Cells ◽

Small Subset ◽

Cell Functions ◽

Tnf Α ◽

Cord Injury ◽

Ifn Γ

Immune responses and neuroinflammation are critically involved in spinal cord injury (SCI). γδ T cells, a small subset of T cells, regulate the inflammation process in many diseases, yet their function in SCI is still poorly understood. In this paper, we demonstrate that mice deficient in γδ T cells (TCRδ−/−) showed improved functional recovery after SCI. γδ T cells are detected at the lesion sites within 24 hours after injury and are predominantly of the Vγ4 subtype and express the inflammatory cytokine IFN-γ. Inactivating IFN-γ signaling in macrophages results in a significantly reduced production of proinflammatory cytokines in the cerebrospinal fluid (CSF) of mice with SCIs and improves functional recovery. Furthermore, treatment of SCI with anti-Vγ4 antibodies has a beneficial effect, similar to that obtained with anti–TNF-α. In SCI patients, γδ T cells are detected in the CSF, and most of them are IFN-γ positive. In conclusion, manipulation of γδ T cell functions may be a potential approach for future SCI treatment.

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