Significant role for IRF3 in both T cell and APC effector functions during T cell responses

65 Background: Obesity is increasingly prevalent and viewed as a critical co-factor in many pathologic conditions due to metabolic, inflammatory and immune perturbations. We performed a multi-species evaluation of the impact of obesity T cell effector functions and markers of immune exhaustion. Methods: We examined the impact of obesity on PD-1 and T cell-mediated responses across different pre-clinical models (tumor, infection, and autoimmune encephalomyelitis [EAE]) and species (mouse, dog, non-human primate, and human). Results: CD4 and CD8 T cells from obese mice, dogs, non-human primates and humans displayed increases in memory T cells and PD-1 expression, as well as impaired proliferative responses compared to lean controls, indicating a greater degree of T cell exhaustion at baseline. Following immunization with myelin oligodendrocyte glycoprotein, obese mice were resistant to induction of EAE, correlating with reduced antigen-specific CD4 T cells in the central nervous system. Administration of anti-PD-1 resulted in restoration of EAE and increased antigen-specific T cell numbers in obese mice. Tumors in obese mice exhibited accelerated growth compared to lean mice, and T cells displayed higher PD-1 expression correlating with RNAseq/molecular signatures of exhaustion compared to tumor-bearing lean mice. PD-1 blockade resulted in marked anti-tumor effects only in obese mice, and not lean. Impaired viral resistance to murine cytomegalovirus (MCMV) resulted was seen in obese mice, associated with increased PD-1/PD-L1 expression, which was reversible by PD-1/PD-L1 blockade. Conclusions: Obesity results in an increase in PD-1/PD-L1 expression and inhibition of T cell responses across species, and blockade not only reverses this inhibition but also leads to markedly augmented T cell effector responses compared to lean counterparts where no effects were observed. These results highlight how the immune system has evolved to control T cell responses using checkpoints contingent on dynamic host conditions and have translational relevance for predicting both efficacy and toxicity in clinical immuno-oncology.

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T Cell-Mediated Immune Responses to AAV and AAV Vectors

Frontiers in Immunology ◽

10.3389/fimmu.2021.666666 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hildegund C. J. Ertl

Keyword(s):

T Cell ◽

Gene Transfer ◽

Immune Responses ◽

De Novo ◽

T Cell Responses ◽

Adeno Associated Virus ◽

Effector Functions ◽

Cell Responses ◽

High Doses

Adeno-associated virus (AAV)-mediated gene transfer has benefited patients with inherited diseases, such as hemophilia B, by achieving long-term expression of the therapeutic transgene. Nevertheless, challenges remain due to rejection of AAV-transduced cells, which in some, but not all, patients can be prevented by immunosuppression. It is assumed that CD8+ T cells induced by natural infections with AAVs are recalled by the AAV vector’s capsid and upon activation eliminate cells expressing the degraded capsid antigens. Alternatively, it is feasible that AAV vectors, especially if given at high doses, induce de novo capsid- or transgene product-specific T cell responses. This chapter discusses CD8+ T cell responses to AAV infections and AAV gene transfer and avenues to prevent their activation or block their effector functions.

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A single dose of the SARS-CoV-2 vaccine BNT162b2 elicits Fc-mediated antibody effector functions and T-cell responses

Cell Host & Microbe ◽

10.1016/j.chom.2021.06.001 ◽

2021 ◽

Author(s):

Alexandra Tauzin ◽

Manon Nayrac ◽

Mehdi Benlarbi ◽

Shang Yu Gong ◽

Romain Gasser ◽

...

Keyword(s):

Single Dose ◽

T Cell ◽

T Cell Responses ◽

Effector Functions ◽

Cell Responses

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SiglecFhigh neutrophils in lung tumor tissues suppress local CD8 T cell responses and limit the efficacy of anti PD-L1 antibodies

10.1101/2021.10.21.464997 ◽

2021 ◽

Author(s):

Francesca Simoncello ◽

Giulia Maria Piperno ◽

Nicoletta Caronni ◽

Tiziana Battini ◽

Ambra Cappelletto ◽

...

Keyword(s):

T Cell ◽

Cd8 T Cells ◽

Gene Editing ◽

Lung Tumor ◽

T Cell Responses ◽

Cd8 T Cell ◽

Effector Functions ◽

Cell Responses ◽

Tumor Tissues ◽

The Impact

Background: Tumor infiltrating neutrophils generally correlates to worst prognosis and refractoriness to immunotherapy yet the complexity and significance of diverse subsets resident in tumor tissues has just begun to emerge. In lung tumors, a network of neutrophils states with graded protumorigenic properties is conserved between mouse and humans and include a subset of mature, long lived cells expressing the sialic-acid-binding protein SiglecF (SiglecFhigh neu). The mechanism of recruitment of SiglecFhigh neu into tumor tissues and the impact on local anti-tumor T cell responses and interference with immunotherapy is still elusive. Methods: We used an immunogenic model of KrasG12D Tp53 null adenocarcinoma of the lung to screen for factors inducing the recruitment of SiglecFhigh neu, followed by gene editing to delete selected candidates. We analyzed frequencies and effector functions of endogenous CD8 T cell responses in controls and SiglecFhigh neu depleted tumors by flow cytometry and functional assays. Tissues fluorescence and confocal imaging of lung sections was used to explore the relative distribution of neu and CD8 T cells. To establish the impact of SiglecFhigh neu on anti-tumoral immune responses we treated cohort of animals with anti-PD-L1 antibodies to evaluate tumor growth in control conditions and under therapy. Results: We found that tumor tissues express high levels of CXCL5, mapping to cancer cells. Upon deletion of chemokine expression by gene editing, the recruitment of SiglecFhigh neu was almost entirely abrogated. In tumors depleted of SiglecFhigh neu, the density of tumor specific endogenous CD8 T cells was 3-fold higher than in controls and showed significantly enhanced activation and effector functions. Importantly, checkpoint blockade with anti PD-L1 antibodies was ineffective in control tumors but showed a significant benefit in SiglecFhigh neu depleted tumors. Conclusion: This study demonstrates that SiglecFhigh neu differentiating in lung tumor tissues inhibit local CD8 T cell responses and interfere with the success of checkpoint blockade. These data suggest that blocking selectively tissue resident neu may promote better responses to immunotherapy.

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A single BNT162b2 mRNA dose elicits antibodies with Fc-mediated effector functions and boost pre-existing humoral and T cell responses

10.1101/2021.03.18.435972 ◽

2021 ◽

Cited By ~ 3

Author(s):

Alexandra Tauzin ◽

Manon Nayrac ◽

Mehdi Benlarbi ◽

Shang Yu Gong ◽

Romain Gasser ◽

...

Keyword(s):

Single Dose ◽

T Cell ◽

Vaccine Efficacy ◽

T Cell Responses ◽

Strong Correlations ◽

Effector Functions ◽

Cell Responses ◽

Health Authorities ◽

Proven Efficacy ◽

Public Health Authorities

AbstractThe standard dosing of the Pfizer/BioNTech BNT162b2 mRNA vaccine validated in clinical trials includes two doses administered three weeks apart. While the decision by some public health authorities to space the doses because of limiting supply has raised concerns about vaccine efficacy, data indicate that a single dose is up to 90% effective starting 14 days after its administration. We analyzed humoral and T cells responses three weeks after a single dose of this mRNA vaccine. Despite the proven efficacy of the vaccine at this time point, no neutralizing activity were elicited in SARS-CoV-2 naïve individuals. However, we detected strong anti-receptor binding domain (RBD) and Spike antibodies with Fc-mediated effector functions and cellular responses dominated by the CD4+ T cell component. A single dose of this mRNA vaccine to individuals previously infected by SARS-CoV-2 boosted all humoral and T cell responses measured, with strong correlations between T helper and antibody immunity. Neutralizing responses were increased in both potency and breadth, with distinctive capacity to neutralize emerging variant strains. Our results highlight the importance of vaccinating uninfected and previously-infected individuals and shed new light into the potential role of Fc-mediated effector functions and T cell responses in vaccine efficacy. They also provide support to spacing the doses of two-vaccine regimens to vaccinate a larger pool of the population in the context of vaccine scarcity against SARS-CoV-2.

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