scholarly journals Multifaceted influence of pre-mitotic cytotoxicity of primed CD8 T cells on immunity and infection

2018 ◽  
Author(s):  
Durga Bhavani Dandamudi ◽  
David A Blair ◽  
Raquel Duque do Nascimento Arifa ◽  
Juan J Lafaille ◽  
Michael L Dustin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Secondary Infection ◽  
Granzyme B ◽  
Adaptive Immune Response ◽  
Lymphocytic Choriomeningitis ◽  
Cell Repertoire ◽  
Adaptive Immune ◽  
Window Of Vulnerability

AbstractGranzyme B mRNA is expressed in primed CD8 T cells within 12 hours, but the consequences of this for the immune response are unknown. We observed that substantial portion of the naïve CD8 T cell repertoire expressed granzyme B and became pre-mitotic cytotoxic cells (PMCs) immediately in response toListeria monocytogenesorLymphocytic choriomeningitis virusinfections. The surprising breadth arose from sufficiency of low potency peptide-MHC to induce granzyme B expression in the context of infection. PMCs killed antigen bearing dendritic cells (DCs) in a granzyme B-dependent but largely perforinindependent fashion between 1-2 days post infection. This terminated antigen presentation at 3 days and resulted in reduced clonal expansion. As additional consequences, we highlight that PMCs reduced the burden of DC-borne infectious agents, but also opened a window of vulnerability for secondary infection. Thus, PMCs serve antigen-specific, regulatory and host defence functions, that are innate-like in scale, at the onset of the adaptive immune response.

Double positive CD4+CD8+ T cells are part of the adaptive immune response against Candida albicans

2019 ◽  
Vol 80 (12) ◽  
pp. 999-1005 ◽  
Author(s):  
Barbara Misme-Aucouturier ◽  
Adel Touahri ◽  
Marjorie Albassier ◽  
Francine Jotereau ◽  
Patrice Le Pape ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Candida Albicans ◽  
Cd8 T Cells ◽  
Adaptive Immune Response ◽  
Double Positive ◽  
Adaptive Immune

scholarly journals Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma

Sarcoma ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
William W. Tseng ◽  
Shruti Malu ◽  
Minying Zhang ◽  
Jieqing Chen ◽  
Geok Choo Sim ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Retroperitoneal Liposarcoma ◽  
Well Differentiated

Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.

scholarly journals Too Much of a Good Thing: High T Cell Count Can Kill Newborns

2019 ◽  
Vol 2 (2) ◽  
pp. 15-16
Author(s):  
Angelina Bustos ◽  
Lai Xu ◽  
Garett Dunsmore ◽  
Shokrollah Elahi
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Adaptive Immune Response ◽  
Spleen Cells ◽  
Robust Immune Response ◽  
Adaptive Immune ◽  
Neonatal Immunity ◽  
Low Exposure

Neonates have a weakened immune system that could be due to low exposure to pathogens resulting in low adaptive immunity and/or purposeful immune suppression to protect the weak neonate from a robust immune response. The purpose of this project is to find preliminary data to further investigate why the immune system of neonates are weaker, and to possibly improve neonatal immunity while protecting against a powerful immune response in the future.  Using processed mice spleen cells that were stained for CD4 and CD8 to be subjected to flow cytometry, an increase in the percent of helper CD4 and killer CD8 T cells were observed as the mice aged. This indicates that neonates do have a weaker immune system. Between healthy mice and mice infected with either Bordetella pertussis or Listeria, a decrease in the percent of CD4 and CD8 T cells were found, which could be because not enough time had passed for an adaptive immune response.

scholarly journals Role of the adaptive immune response in sepsis

2020 ◽  
Vol 8 (S1) ◽  
Author(s):  
Jack Brady ◽  
Shahd Horie ◽  
John G. Laffey
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
Immune Cell ◽  
Secondary Infection ◽  
Adaptive Immune Response ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Inflammatory Phase ◽  
Adaptive Immune Cells

AbstractSepsis is a syndrome of shock and dysfunction of multiple vital organs that is caused by an uncontrolled immune response to infection and has a high mortality rate. There are no therapies for sepsis, and it has become a global cause for concern. Advances in patient care and management now mean that most patients survive the initial hyper-inflammatory phase of sepsis but progress to a later immunosuppressed phase, where 30% of patients die due to secondary infection. Deficits in the adaptive immune response may play a major role in sepsis patient mortality. The adaptive immune response involves a number of cell types including T cells, B cells and dendritic cells, all with immunoregulatory roles aimed at limiting damage and returning immune homeostasis after infection or insult. However, in sepsis, adaptive immune cells experience cell death or exhaustion, meaning that they have defective effector and memory responses ultimately resulting in an ineffective or suppressed immune defence. CD4+ T cells seem to be the most susceptible to cell death during sepsis and have ensuing defective secretory profiles and functions. Regulatory T cells seem to evade apoptosis and contribute to the immune suppression observed with sepsis. Preclinical studies have identified a number of new targets for therapy in sepsis including anti-apoptotic agents and monoclonal antibodies aimed at reducing cell death, exhaustion and maintaining/restoring adaptive immune cell functions. While early phase clinical trials have demonstrated safety and encouraging signals for biologic effect, larger scale clinical trial testing is required to determine whether these strategies will prove effective in improving outcomes from sepsis.

IMMU-44. AN IMMUNOTHERAPEUTIC VACCINE COMPOSED OF IRRADIATED WHOLE TUMOR CELLS PULSED WITH MANNAN-BAM, TLR LIGANDS AND ANTI-CD40 ANTIBODY INDUCES POTENT IMMUNE RESPONSE IN PRECLINICAL GBM ANIMAL MODEL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi102
Author(s):  
Herui Wang ◽  
Rogelio Medina ◽  
Juan Ye ◽  
Pashayar Lookian ◽  
Ondrej Uher ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Therapeutic Efficacy ◽  
Poly I:C ◽  
Control Group ◽  
Complete Regression ◽  
Adaptive Immune

Abstract Despite numerous therapeutic advances, the treatment of glioblastoma multiforme (GBM) remains a challenge, with current 5-year survival rates estimated at 4%. Multiple characteristic elements of GBM contribute to its treatment-resistance, including its low immunogenicity and its highly immunosuppressive microenvironment that can effectively disarm adaptive immune responses. Hence, therapeutic strategies that aim to boost T-lymphocyte mediated responses against GBM are of great therapeutic value. Herein, we present a therapeutic vaccination strategy that promotes the phagocytosis of tumor cells, enhances tumor antigen presentation, and induces a tumor-specific adaptive immune response. This strategy consists of vaccinations with irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists (Mannan-BAM), TLR ligands [LTA, Poly (I:C), and R-848], and anti-CD40 antibody (collectively abbreviated as rWTC-MBTA). We evaluated the therapeutic efficacy of rWTC-MBTA strategy in a mouse syngeneic GL261 orthotopic GBM tumor model. rWTC-MBTA or vehicle control were administered subcutaneously over the right foreleg three days after intracranial injection of GL261 cells. Complete regression (CR) of intracranial tumors was achieved in 70% (7/10) of rWTC-MBTA treated animals while none survived in the control group. Immunophenotyping analyses of peripheral lymph nodes and brain tumors of rWTC-MBTA treated mice demonstrated: (1) increased mature dendritic cells and MHC II+ monocytes; (2) increased effector (CD62L-CD44+) CD4-T and CD8-T cells; (3) increased cytotoxic IFNγ-, TNFα-, and granzyme B-secreting CD4-T and CD8-T cells. Of note, the therapeutic efficacy of rWTC-MBTA disappeared in CD4-T and/or CD8-T lymphocyte depleted mice. Three mice that achieved CR were rechallenged with 50k GL261 cells intracranially 14 months after the last rWTC-MBTA treatment and all rechallenged animals resisted GL261 tumor development, confirming the establishment of long-term immunological memory against GL261 tumor cells. Collectively, our study demonstrated that rWTC-MBTA strategy can effectively activate antigen presenting cells and induce more favorable T-cell signatures in the GBM tumors.

scholarly journals A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1749
Author(s):  
Jing-Jing Wang ◽  
Michelle Kwan-Yee Siu ◽  
Yu-Xin Jiang ◽  
Thomas Ho-Yin Leung ◽  
David Wai Chan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Combined Treatment ◽  
In Vivo Studies ◽  
Immune Checkpoints ◽  
Ovarian Cancer Cells

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan–Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

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