scholarly journals OVX836 Heptameric Nucleoprotein Vaccine Generates Lung Tissue-Resident Memory CD8+ T-Cells for Cross-Protection Against Influenza

2021 ◽  
Vol 12 ◽  
Author(s):  
Judith Del Campo ◽  
Julien Bouley ◽  
Marion Chevandier ◽  
Carine Rousset ◽  
Marjorie Haller ◽  
...  
Keyword(s):  
T Cells ◽  
Recombinant Protein ◽  
Dna Sequence ◽  
Cd8 T Cells ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
Protein Vaccine ◽  
Memory Cd8 T Cells

Tissue-resident memory (TRM) CD8+ T-cells play a crucial role in the protection against influenza infection but remain difficult to elicit using recombinant protein vaccines. OVX836 is a recombinant protein vaccine, obtained by the fusion of the DNA sequence of the influenza A nucleoprotein (NP) to the DNA sequence of the OVX313 heptamerization domain. We previously demonstrated that OVX836 provides broad-spectrum protection against influenza viruses. Here, we show that OVX836 intramuscular (IM) immunization induces higher numbers of NP-specific IFNγ-producing CD8+ T-cells in the lung, compared to mutant NP (NPm) and wild-type NP (NPwt), which form monomeric and trimeric structures, respectively. OVX836 induces cytotoxic CD8+ T-cells and high frequencies of lung TRM CD8+ T-cells, while inducing solid protection against lethal influenza virus challenges for at least 90 days. Adoptive transfer experiments demonstrated that protection against diverse influenza subtypes is mediated by NP-specific CD8+ T-cells isolated from the lung and spleen following OVX836 vaccination. OVX836 induces a high number of NP-specific lung CD8+ TRM-cells for long-term protection against influenza viruses.

scholarly journals Requirement of Mature Dendritic Cells for Efficient Activation of Influenza A-Specific Memory CD8+T Cells

2000 ◽  
Vol 165 (3) ◽  
pp. 1182-1190 ◽  
Author(s):  
Marie Larsson ◽  
Davorka Messmer ◽  
Selin Somersan ◽  
Jean-François Fonteneau ◽  
Sean M. Donahoe ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Influenza A ◽  
Memory Cd8 T Cells ◽  
Specific Memory

scholarly journals Long-Term Maintenance of Virus-Specific Effector Memory CD8+T Cells in the Lung Airways Depends on Proliferation

2002 ◽  
Vol 169 (9) ◽  
pp. 4976-4981 ◽  
Author(s):  
Robert J. Hogan ◽  
Linda S. Cauley ◽  
Kenneth H. Ely ◽  
Tres Cookenham ◽  
Alan D. Roberts ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Effector Memory ◽  
Memory Cd8 T Cells ◽  
Specific Effector ◽  
Lung Airways ◽  
Term Maintenance

scholarly journals The IL-2/IL-15 Mimetic NL-201 Prevents Myeloma Relapse after ASCT By Expanding Highly Cytolytic T Cells in the Bone Marrow That Are Resistant to Exhaustion

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1609-1609
Author(s):  
Simone A Minnie ◽  
Nicole S Nemychenkov ◽  
Shuichiro Takahashi ◽  
Christine R Schmidt ◽  
Samuel RW Legg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Granzyme B ◽  
Cell Number ◽  
Memory Cd8 T Cells ◽  
Time Of Harvest

Abstract Multiple myeloma (MM) is a bone marrow (BM) resident hematological malignancy that is becoming increasingly recognized as one amenable to immunotherapy, although no therapies have yet provided durable, long-term disease control. Autologous stem cell transplantation (ASCT), the standard of care in eligible patients, provides a window for intervention with immunotherapy due to the induction of inflammation in the context of lymphodepletion at a time where there is also minimal residual disease and a disrupted tumor microenvironment (TME). We have previously established that the addition of T cells to BM grafts results in enhanced long-term myeloma control post-transplant in mice. Novel approaches aimed at improving and/or expanding the endogenous T cell response early post-ASCT may therefore prove highly effective with the benefit of avoiding ex vivo processing associated with other cellular therapies. To explore this, we utilized the IL-2/IL-15 mimetic NL-201: a de novo cytokine mimetic that signals via the beta and gamma subunits of the IL-2 receptor without engaging IL-2Rα (CD25). In pre-clinical studies, NL-201 has demonstrated the ability to signal to effector CD4 and CD8 T cells while avoiding the toxicity usually associated with IL-2 signaling via IL-2Rα. We hypothesized that NL-201 would enhance control of myeloma progression by stimulating T cell proliferation and activation early post-ASCT. We transplanted lethally irradiated Vk*MYC myeloma-bearing B6 recipients with BM and T cells graft from B6 donors and administered NL-201 from D+7 to week 6 (225 μg/kg weekly I.P). NL-201 promoted potent anti-myeloma immunity that was dependent on CD4 and CD8 T cells, but not NK cells (median survival was 68 days for control mice, unreached at >120 days for NL-201 alone or with NK depletion, 86 days for NL-201 with CD8 depletion, and 74 days with CD4 depletion; PBS vs NL-201 p<0.01; PBS vs NL-201 + αNK1.1 p<0.01; NL-201 vs NL-201 + αCD4 or αCD8 p<0.05). To further elucidate potential mechanisms of action we harvested BM from PBS and NL-201-treated mice 2 days after the last dose was administered and performed comprehensive immunophenotyping with high parameter flow cytometry. We grouped recipients based on whether they had controlled myeloma (MM-controlled) or had active disease progression at the time of harvest (MM-relapsed) to reveal immunological phenotypes that were dependent and independent of myeloma in the TME. In these experiments, all NL-201-treated recipients had controlled myeloma at time of harvest. Mechanistically, NL-201 significantly expanded the total number of CD8 T cells in the BM compared to PBS-treated mice with controlled or relapsed MM (PBS-treated mean CD8 T cell number was 1.0 x 10 5/femur vs 7.7 x 10 5/femur in NL-201-treated mice) but did not impact CD8 T cell number in peripheral blood. Memory CD8 T cells (CD44+CD62L+) were preferentially expanded, while the frequency of exhausted CD8 T cells (TOX +PD-1 +TIGIT +CD39 +; T EX) was reduced in NL-201-treated mice compared to both PBS-treated MM-relapsed and MM-controlled mice (75% T EX in PBS MM-relapsed, 15% PBS MM-controlled, 2% in NL-201; p<0.001). Surprisingly, >80% of the memory CD8 T cells in NL-201-treated mice produced granzyme B compared to <10% in PBS-treated mice. Granzyme B production was also observed in conventional CD4 T cells in response to NL-201 treatment, and the frequency of regulatory T cells was reduced by 50% after NL-201 compared to PBS MM-controlled and MM-relapsed mice (p<0.001). NL-201 expanded bone marrow resident cytotoxic memory CD8 and CD4 T cells that are resistant to exhaustion, whilst reducing the frequency of regulatory T cells in the BM TME. Together, these data highlight the promising therapeutic potential of NL-201 in multiple myeloma and support testing NL-201 in clinical trials for the treatment of hematological malignancies. Disclosures Hill: NapaJen Pharma: Consultancy; Roche: Research Funding; Syndax Pharmaceuticals: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Applied Molecular Transport: Research Funding; Compass Therapeutics: Research Funding; NeoLeukin Therapeutics: Consultancy; Generon Corporation: Consultancy.

scholarly journals Topical exposure to triclosan inhibits Th1 immune responses and reduces T cells responding to influenza infection in mice

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244436
Author(s):  
Hillary L. Shane ◽  
Sreekumar Othumpangat ◽  
Nikki B. Marshall ◽  
Francoise Blachere ◽  
Ewa Lukomska ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Healthcare Workers ◽  
Influenza A ◽  
Influenza Infection ◽  
Statistical Significance ◽  
Lethal Dose ◽  
Respiratory Pathogens ◽  
Increased Risk

Healthcare workers concurrently may be at a higher risk of developing respiratory infections and allergic disease, such as asthma, than the general public. Increased incidence of allergic diseases is thought to be caused, in part, due to occupational exposure to chemicals that induce or augment Th2 immune responses. However, whether exposure to these chemical antimicrobials can influence immune responses to respiratory pathogens is unknown. Here, we use a BALB/c murine model to test if the Th2-promoting antimicrobial chemical triclosan influences immune responses to influenza A virus. Mice were dermally exposed to 2% triclosan for 7 days prior to infection with a sub-lethal dose of mouse adapted PR8 A(H1N1) virus (50 pfu); triclosan exposure continued until 10 days post infection (dpi). Infected mice exposed to triclosan did not show an increase in morbidity or mortality, and viral titers were unchanged. Assessment of T cell responses at 10 dpi showed a decrease in the number of total and activated (CD44hi) CD4+ and CD8+ T cells at the site of infection (BAL and lung) in triclosan exposed mice compared to controls. Influenza-specific CD4+ and CD8+ T cells were assessed using MHCI and MHCII tetramers, with reduced populations, although not reaching statistical significance at these sites following triclosan exposure. Reductions in the Th1 transcription factor T-bet were seen in both activated and tetramer+ CD4+ and CD8+ T cells in the lungs of triclosan exposed infected mice, indicating reduced Th1 polarization and providing a potential mechanism for numerical reduction in T cells. Overall, these results indicate that the immune environment induced by triclosan exposure has the potential to influence the developing immune response to a respiratory viral infection and may have implications for healthcare workers who may be at an increased risk for developing infectious diseases.

scholarly journals Influenza infection results in local expansion of memory CD8+T cells with antigen non-specific phenotype and function

2013 ◽  
Vol 175 (1) ◽  
pp. 79-91 ◽  
Author(s):  
Gail D. Sckisel ◽  
Julia K. Tietze ◽  
Anthony E. Zamora ◽  
Hua-Hui Hsiao ◽  
Stephen O. Priest ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Influenza Infection ◽  
Memory Cd8 T Cells ◽  
Local Expansion ◽  
And Function

scholarly journals Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Isaac J jensen ◽  
Xiang Li ◽  
Patrick W McGonagill ◽  
Qiang Shan ◽  
Micaela G Fosdick ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
Cytokine Storm ◽  
Protective Function ◽  
Memory Cd8 T Cells ◽  
Memory Cd8 T Cell

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.

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