When friendly forces become enemies: Scientists blunt the impact of natural killer cells to increase vaccine effectiveness

PD-1 dependent NK cell regulation of CD8⁺T-cells. C57BL/6 mice were infected with an adenoviral vector encoding the HBV genome and treated with anti-NK1.1 (⍺NK) or isotype control antibodies prior to therapeutic vaccination. Intrahepatic lymphocytes were harvested 14 days after immunization. (A) Quantitative real-time PCR analysis of HBsAg mRNA extracted from the liver of infected mice. (B) Representative plot of CD8⁺T-cells isolated from the spleen of CD45.2 PD-1KO or CD45.1 wild-type (WT) mice were transferred to recipients of opposite congenic mice one day before therapeutic vaccination. Examples of PD-1 and IFN . expressionsyou production in transferred PD-1KO and WT CD8+ T cells. *, pScience Translational Medicine (2022). DOI: 10.1126/scitranslmed.abi4670

Scientists have found that the body’s own natural killer cells can suppress the immune benefits of therapeutic vaccines, a problem that can predispose to inoculation against chronic viral infections and cancer.

Indeed, the scientific literature is full of examples of effective vaccines sometimes proving to be impotent. More and more reasons lead to enemies within the body itself: friends turned enemies.

Scientists at University College London have delved into the puzzle and have turned to animal models to decipher how natural killer cells inadvertently blunt the benefits of vaccines.

In Translated Medical Sciences, Dr. Mariana O. Diniz and colleagues report that natural killer cells can react so violently after vaccination that they negatively impact an important constituent of the immune response—CD8+T cells. This vital population can become overworked and exhausted, Diniz and his colleagues found, a phenomenon that renders vaccinations ineffective.

“Therapeutic vaccines for chronic infections have reduced efficacy due to the presence of depleted T cells and [an] environment that limits the vaccine response,” Diniz wrote, noting that the problem always starts with natural killer cell aggression.

Working with a mouse model, Diniz and colleagues have found that the combination treatment can promote a robust immune response after vaccination by acting on natural killer cells. The strategy, the team said, could eventually prove useful in the design and improvement of therapeutic vaccines for chronic viral infections and cancer.

“A better understanding of the mechanisms that regulate CD8+T cell responses to therapeutic vaccines is needed to develop approaches to improve vaccine efficacy for chronic viral infections and cancer,” Diniz and the UCL team assert in the journal.

Part of their research involved gaining in-depth knowledge of the natural killer cells themselves, a population whose name alone can conjure up powerful images of destruction.

Natural killer cells are produced in the bone marrow as well as other sites throughout the body. Also known simply as natural killers, or simply plain old NK cells, this population is a type of white blood cell that contains granules—microscopic particles—with enzymes capable of killing tumor cells or virus-infected cells.

Natural killers were originally thought to develop exclusively in the bone marrow, but relatively recent evidence in humans and mice suggests that these cells can also develop and mature in secondary lymphoid tissues, such as the tonsils, spleen and lymph nodes.

The killer is a type of immune cell and is an important constituent of the innate immune system, the body’s rapid response network. It is present at birth and is the first immune response in the event of infection or cancer. The innate system exists separately from the adaptive immune system, which appears around 12 months of age. The adaptive system, also known as acquired immunity, consists of a specialized array of immune cells—T cells, B cells, and protein antibodies—that seek out and destroy foreign invaders.

While the innate immune system is renowned for its rapid response, the adaptive is known for its memory power and its ability to pounce on future threats more quickly by relying on its memories of the same invaders from the past.

The goal of UCL’s research is to turn natural killer cells from enemies into friends in vaccination situations for chronic conditions. The team’s investigation revealed that natural killers impair T-cell responses in mice to ChAdOx1-HBV, an experimental vaccine for chronic hepatitis B virus infection.

The scientists found that hepatitis B infection increased the expression of the protein PD-L1 on the surface of natural killer cells in the liver, which in turn suppressed vaccine-prepared T cells.

However, depletion of natural killer cells increased T cell response in mice after vaccination. Alternatively, the researchers found that they could convert natural killer cells into immune-boosting helpers by administering anti-PD-L1 antibodies prior to vaccination, leading to a stronger hepatitis B virus-specific T cell response.

The team then applied a similar approach to cell samples from patients with chronic hepatitis B and found that the strategy could also benefit humans.

“Our findings describe combination immunotherapy that may enhance response to therapeutic vaccination in chronic hepatitis B and highlight the importance of PD-L1-dependent T cell regulation by cytokine-activated natural killer cells,” Diniz concludes.

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Maximizing the effectiveness of therapeutic vaccines one step closer

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Further information:
Mariana O. Diniz et al, NK cells limiting therapeutic vaccine-induced CD8+ T cell immunity in a PD-L1-dependent manner, Translated Medical Sciences (2022). DOI: 10.1126/scitranslmed.abi4670

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