Enforced Asymmetric Cell Division Could Boost Memory of CD8+ T Cells

New research suggests a strategy to manipulate T cell division could help CD8+ T cells remember how to fight off pathogens for an extended period of time.

Writing in Science Immunology, investigators from ETH Zurich say the strategy could have implications for cancer treatment and vaccine development.

After successfully fighting off disease, most CD8+ T cells simply die. Some, however, turn into memory T cells—long-lasting, self-renewing cells that are able to recognize and attack pathogens in subsequent infections. Although scientists have yet to fully understand the causes of T cell differentiation, they are beginning to learn more about asymmetric cell division (ACD). In ACD, memory T cells are divided and 2 daughter cells are produced. One daughter cell differentiates into an effector cell, and the other into a cell that shares key characteristics with memory cells. Specifically, this second category of daughter cell maintains “stemness,” the ability to produce diverse progeny.

“Stemness is extremely relevant for immune responses, as it is a feature of memory cells,” co-authors Annette Oxenius, PhD, and Mariana Borsa, PhD, told Contagion®.

Annette Oxenius, PhD

Oxenius and Borsa set out to evaluate whether enforcing ACD in CD8+ T cells would impact T cell differentiation and memory. Building upon research by Rafi Ahmed, PhD, of Emory University, the Swiss investigators found they could use the immunosuppressive drug rapamycin to temporarily inhibit the molecule mTOR. This inhibition resulted in enhanced rates of ACD among naive and memory T cells. Furthermore, they found T cells that resulted from this enforced ACD had higher memory potential and longer survival. After rapamycin treatment was stopped, mTOR activity was re-established.

“The novelty in our strategy relies on the fact that T cells are exposed to rapamycin treatment shortly and transiently (which results in enhanced ability to divide asymmetrically), with long-term benefits, which brings a great translational potential in the context of adoptive transfer therapies used to fight cancer,” Oxenius and Borsa said.

The investigators found that the progeny that resulted from the enforced ACD had better re-expansion when re-encountering the antigen, the “memory daughters” showed higher expressions of genes linked to a fully-formed memory cell phenotype, and the cells had better homing to secondary lymphoid organs and better survival.

“We can't predict exactly how long an individual memory CD8 T cell would survive in a host before encountering its antigen again—in our murine model we have done experiments with positive results after waiting for maximum of 3 months,” they said. “However, our strategy definitely generates progenies with increased frequencies of cells exhibiting memory features, while also improving their quality.”

The strategy could have very significant clinical implications, Oxenius and Borsa said. As previously mentioned, the strategy could be used in adoptive transfer therapies, in which CD8 T cells are manipulated so as to boost the body’s immune response against cancer.

“In a very simple way, cells from a cancer patient could be isolated, activated in vitro, transiently treated with rapamycin (which will lead to progenies with boosted memory features), and transferred back to the patient, potentially improving the immune responses against a certain tumor,” they said.

Another potential result of this research is improved vaccines, since effective vaccines rely on long-lasting memory cells.

“However, effective design of vaccines targeting CD8 T cell responses still remains a challenge,” they said.