CD8 cells. A, Representative graphs showed the gating strategy to analyze tetramer positive cells. Live CD3+CD4–CD8+ cells were gated and CD56–CD94– cells were selected for evaluation. B, Lack of NKG2A-CD94 or NKG2C-CD94 tetramer binding to HLA-E bound SARS CoV-2 peptides. C-D, Representative SARS-CoV-2 CD8 clones underwent the normal tetramer staining procedure (C) or a modified-wash procedure (D), as outlined in the Methods section. The histograms depicted the intensity of tetramer staining of a SARS-CoV-2 CD8 clone (red), an irrelevant HLA-E-restricted HIV-specific CD8 clone, a tetramer negative clone (blue) and a no tetramer staining control (gray). Credit: Science Immunology (2023). DOI: 10.1126/sciimmunol.abl8881″>
Identification of HLA-E restricted SARS-CoV-2-specific CD8 cells. A, Representative graphs showed the gating strategy to analyze tetramer positive cells. Live CD3+CD4–CD8+ cells were gated and CD56–CD94– cells were selected for evaluation. B, Lack of NKG2A-CD94 or NKG2C-CD94 tetramer binding to HLA-E bound SARS CoV-2 peptides. C-D, Representative SARS-CoV-2 CD8 clones underwent the normal tetramer staining procedure (C) or a modified-wash procedure (D), as outlined in the Methods section. The histograms depicted the intensity of tetramer staining of a SARS-CoV-2 CD8 clone (red), an irrelevant HLA-E-restricted HIV-specific CD8 clone, a tetramer negative clone (blue) and a no tetramer staining control (gray). Credit: Science Immunology (2023). DOI: 10.1126/sciimmunol.abl8881
An obscure class of molecules, part of the vast system that helps the human body distinguish “self” from “non-self,” may also hold the key to stopping SARS-CoV-2 from commandeering healthy cells, scientists have found in an elegant series of experiments.
The research, published in Science Immunology, was led by the University of Oxford in the U.K., where scientists have homed in on a class of molecules whose job is preventing the immune system from attacking healthy cells. The spotlighted molecules belong to the human leukocyte antigen class of proteins, part of the major histocompatibility complex. The human leukocyte antigen proteins are known by the shorthand description HLA.
Within the crucial HLA family, there are several classes of HLA molecules, and each class can be found on specific types of cells. For example, HLA class I molecules are found on the surface of almost all nucleated cells; class II are on B lymphocytes, dendritic cells, macrophages, monocytes, and thymic epithelial cells, among others. These HLA groups, or classes of HLA molecules, are known as classical HLA proteins.
It is HLA antigens involving donors and recipients that are analyzed for organ transplants. The closer the match, the more likely that the transplant will be successful. HLA proteins, in general, enable the body to distinguish “self” from “non-self,” and prevent autoimmune attacks against normal cells.
Even though past research has demonstrated that SARS-CoV-2 infection automatically tamps down—downregulates—classical HLA proteins to prevent the immune system from recognizing infected cells, it has remained unclear whether SARS-CoV-2 truly affects all HLA classes in the same way. For example, the behavior of an obscure subset of HLA class I molecules, defined as HLA-E, is not tamped down by the virus the way classical HLA molecules are, suggesting a possible covert immune response against SARS-CoV-2.
HLA-E is expressed on natural killer cells and on CD8+ T cells. The Oxford team was interested in the population known as HLA-E-restricted CD8+ T cells, a fierce but clandestine army of T cells potentially capable of quashing cells infected with SARS-CoV-2. It’s the activity of these T cells that may explain why some people quickly thwart COVID-19.
Still, as exciting as the possibility of a secret weapon against the coronavirus seemed in theory, the activity of HLA-E during SARS-CoV-2 infection had been murky until the new Oxford research.
Dr. Hongbing Yang and a team of Oxford colleagues have examined blood samples from patients with COVID-19 and identified five peptides—protein fragments—that induce HLA-E-restricted killer T cell activity. HLA-E is an important regulator of natural killer cell and cytotoxic T lymphocyte activation and inhibition. HLA-E, the team found in a series of experiments, can respond to and initiate an immune response against SARS-CoV-2-infected cells.
“We describe five peptides from SARS-CoV-2 that elicited HLA-E–restricted CD8+ T cell responses in convalescent patients with coronavirus disease 2019,” wrote Dr. Hongbing Yang in the research paper, referring to patients with COVID-19.
Yang and his Oxford team demonstrated in their research how HLA-E is critical during SARS-CoV-2 infection. Indeed, the HLA system is controlled by genes on chromosome 6, which encode the activity of all HLA cell-surface proteins that help regulate the immune response. The Oxford team zeroed in on HLA-E because it is known for its capacity to orchestrate the destruction of cells compromised by replicating viruses.
In the laboratory, Yang and colleagues discovered that clones of the HLA-E-specific CD8+ T cells, derived from COVID-19 patients, recognized SARS-CoV-2–infected cells and suppressed viral replication. But, also confirmed in the laboratory was the tamping down of classical HLA molecules by SARS-CoV-2. This is the activity that allows the coronavirus to overwhelm vulnerable cells while eluding the immune system—the so-called immune escape. But this did not happen in HLA-E cell lines, particularly those from primary human airway epithelial cells, the study found.
Further analyses of primary human lung epithelial cells showed that SARS-CoV-2 exposure caused downregulation of HLA-Ia, but not HLA-E. HLA-E peptide-derived CD8+ T cell clones, which expressed diverse T cell receptors, and suppressed SARS-CoV-2 replication in human lung epithelial cells. “It is possible that the normal balance, which is strongly in favor of classically restricted T cells, is disturbed in SARS-CoV-2 infection and that HLA-E-restricted T cells then could contribute to control of the virus in this infection,” Yang and colleagues theorized in the study.
Their research has opened a new window of understanding into the HLA complex in general during SARS-CoV-2 infection, and more specifically, HLA-E’s unique response. Yang and collaborators discovered that HLA-E-restricted killer T cells persisted at a robust level, and that the HLA-E T cells were capable of suppressing viral replication.
These findings suggest that SARS-CoV-2–specific HLA-E–restricted CD8+ T cells may be advantageous when classical HLA molecules are downregulated by SARS-CoV-2. Increasing the activity of HLA-E-restricted molecules could be exploited through a targeted vaccine, especially for people who are immunocompromised, such as people 65 and older, or those who have chronic diseases.
“Induction of HLA-E-restricted T cell responses by vaccines focused on the universally presented epitopes could be an attractive possibility,” Yang concluded.
More information:
Hongbing Yang et al, HLA-E–restricted SARS-CoV-2–specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation, Science Immunology (2023). DOI: 10.1126/sciimmunol.abl8881
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Study: The human body may possess a secret weapon against SARS-CoV-2 (2023, August 17)
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NAIROBI, Kenya (AP) — The body of Ugandan Olympic athlete Rebecca Cheptegei — who died after being set on fire by her partner in Kenya — was received Friday by family and anti-femicide crusaders, ahead of her burial a day later.
Cheptegei’s family met with dozens of activists Friday who had marched to the Moi Teaching and Referral Hospital’s morgue in the western city of Eldoret while chanting anti-femicide slogans.
She is the fourth female athlete to have been killed by her partner in Kenya in yet another case of gender-based violence in recent years.
Viola Cheptoo, the founder of Tirop Angels – an organization that was formed in honor of athlete Agnes Tirop, who was stabbed to death in 2021, said stakeholders need to ensure this is the last death of an athlete due to gender-based violence.
“We are here to say that enough is enough, we are tired of burying our sisters due to GBV,” she said.
It was a somber mood at the morgue as athletes and family members viewed Cheptegei’s body which sustained 80% of burns after she was doused with gasoline by her partner Dickson Ndiema. Ndiema sustained 30% burns on his body and later succumbed.
Ndiema and Cheptegei were said to have quarreled over a piece of land that the athlete bought in Kenya, according to a report filed by the local chief.
Cheptegei competed in the women’s marathon at the Paris Olympics less than a month before the attack. She finished in 44th place.
Cheptegei’s father, Joseph, said that the body will make a brief stop at their home in the Endebess area before proceeding to Bukwo in eastern Uganda for a night vigil and burial on Saturday.
“We are in the final part of giving my daughter the last respect,” a visibly distraught Joseph said.
He told reporters last week that Ndiema was stalking and threatening Cheptegei and the family had informed police.
Four in 10 women or an estimated 41% of dating or married Kenyan women have experienced physical or sexual violence perpetrated by their current or most recent partner, according to the Kenya Demographic and Health Survey 2022.
TEL AVIV, Israel (AP) — A rare Bronze-Era jar accidentally smashed by a 4-year-old visiting a museum was back on display Wednesday after restoration experts were able to carefully piece the artifact back together.
Last month, a family from northern Israel was visiting the museum when their youngest son tipped over the jar, which smashed into pieces.
Alex Geller, the boy’s father, said his son — the youngest of three — is exceptionally curious, and that the moment he heard the crash, “please let that not be my child” was the first thought that raced through his head.
The jar has been on display at the Hecht Museum in Haifa for 35 years. It was one of the only containers of its size and from that period still complete when it was discovered.
The Bronze Age jar is one of many artifacts exhibited out in the open, part of the Hecht Museum’s vision of letting visitors explore history without glass barriers, said Inbal Rivlin, the director of the museum, which is associated with Haifa University in northern Israel.
It was likely used to hold wine or oil, and dates back to between 2200 and 1500 B.C.
Rivlin and the museum decided to turn the moment, which captured international attention, into a teaching moment, inviting the Geller family back for a special visit and hands-on activity to illustrate the restoration process.
Rivlin added that the incident provided a welcome distraction from the ongoing war in Gaza. “Well, he’s just a kid. So I think that somehow it touches the heart of the people in Israel and around the world,“ said Rivlin.
Roee Shafir, a restoration expert at the museum, said the repairs would be fairly simple, as the pieces were from a single, complete jar. Archaeologists often face the more daunting task of sifting through piles of shards from multiple objects and trying to piece them together.
Experts used 3D technology, hi-resolution videos, and special glue to painstakingly reconstruct the large jar.
Less than two weeks after it broke, the jar went back on display at the museum. The gluing process left small hairline cracks, and a few pieces are missing, but the jar’s impressive size remains.
The only noticeable difference in the exhibit was a new sign reading “please don’t touch.”
VICTORIA – The British Columbia government is partnering with a bear welfare group to reduce the number of bears being euthanized in the province.
Nicholas Scapillati, executive director of Grizzly Bear Foundation, said Monday that it comes after months-long discussions with the province on how to protect bears, with the goal to give the animals a “better and second chance at life in the wild.”
Scapillati said what’s exciting about the project is that the government is open to working with outside experts and the public.
“So, they’ll be working through Indigenous knowledge and scientific understanding, bringing in the latest techniques and training expertise from leading experts,” he said in an interview.
B.C. government data show conservation officers destroyed 603 black bears and 23 grizzly bears in 2023, while 154 black bears were killed by officers in the first six months of this year.
Scapillati said the group will publish a report with recommendations by next spring, while an independent oversight committee will be set up to review all bear encounters with conservation officers to provide advice to the government.
Environment Minister George Heyman said in a statement that they are looking for new ways to ensure conservation officers “have the trust of the communities they serve,” and the panel will make recommendations to enhance officer training and improve policies.
Lesley Fox, with the wildlife protection group The Fur-Bearers, said they’ve been calling for such a committee for decades.
“This move demonstrates the government is listening,” said Fox. “I suspect, because of the impending election, their listening skills are potentially a little sharper than they normally are.”
Fox said the partnership came from “a place of long frustration” as provincial conservation officers kill more than 500 black bears every year on average, and the public is “no longer tolerating this kind of approach.”
“I think that the conservation officer service and the B.C. government are aware they need to change, and certainly the public has been asking for it,” said Fox.
Fox said there’s a lot of optimism about the new partnership, but, as with any government, there will likely be a lot of red tape to get through.
“I think speed is going to be important, whether or not the committee has the ability to make change and make change relatively quickly without having to study an issue to death, ” said Fox.
This report by The Canadian Press was first published Sept. 9, 2024.
