Immunologists from St. Jude Children's Research Hospital have plotted a previously unfamiliar biological pathway through which the immune system produces T cells that destroy viruses, bacteria, and tumor cells.
From left: Hongbo Chi, Ph.D., Hongling Huang, Ph.D., and PeiPei Zhou, Ph.D., all of St. Jude Immunology, have mapped the previously unknown biological machinery by which the immune system generates T cells that kill bacteria, viruses, and tumor cells. Image Credit: St. Jude Children’s Research Hospital.
These discoveries hold many implications for how the adaptive immune system reacts to infections to produce such memory T cells. Experiments were performed that showed mechanisms that prevent the development of long-lasting memory T cells that continuously renew themselves to protect the body over time. Inhibiting such inhibitory mechanisms with genetic or pharmacological methods could improve immunity against cancers and infections.
The team has also identified a subtype of memory T cells, which they termed terminal effector prime cells. Mapping the mechanism that regulates these cells gives provides the potential to exploit this control pathway to improve the capacity of the immune system to kill cancer cells and microorganisms. In addition, mapping the regulatory pathway has given an insight that diet may have a greater impact on immune function than previously believed.
The study, headed by Hongbo Chi, PhD, from the Department of Immunology, was recently published in the Cell journal. The first authors of the study are Hongling Huang, Ph.D., and Peipei Zhou, Ph.D., Immunology.
CRISPR-assisted mapping of the metabolic machinery
When the body experiences an infection, the immune system starts to produce effector T cells to attack the invasive viruses or bacteria. There are two kinds of effector T cells. One is the memory precursor cells, which can grow into memory T cells that remain for a long time to defend the body. These are the T cells that are generated by vaccines. The other type are short-lived terminal effector T cells, which have instant cytotoxic activity.
In this analysis, the research team tried to map the metabolic pathway that regulates how the immune system chooses to create memory T-cell. Chi and his collaborators targeted the less familiar pathways that suppress the production of this form of T cell.
The team employed a gene-manipulating technology, known as CRISPR, to sift through over 3,000 metabolism-controlling genes in mouse cells. The objective was to identify genes that controlled the “fate” of memory T cells and effector T cells.
Nutrients play an unexpected role in T cell fate
The study demonstrated a previously unfamiliar role that nutrients, like certain sugars as well as amino acids, play in controlling the fate of regulating T cells. To the investigators; amazement, the study identified nutrient-associated pathways that inhibited the production of memory T cells.
The preconceived notion about nutrients' role in immune cell function was that the cells rely on nutrients as an energy source and for building blocks. But our study provides another view--that nutrients are involved in inhibitory pathways, and that deprivation of certain nutrients or metabolites might be good for adaptive immunity.”
Hongling Huang, PhD, Study First Author, Department of Immunology, St. Jude Children’s Research Hospital
“It seems to suggest that what you eat and drink may have a greater influence on immune function than previously appreciated. This will be an important pathway for future research,” Huang added.
New T cell subtype identified
The analyses have uncovered a novel subtype of the effector T-cell, which they dubbed the terminal effector primary cells. Inhibiting the development of these cells could be crucial to improving the immunity mediated by T cells. The researchers’ study detected a mechanism that regulates the conversion of developing T cells from the intermediate phase to the mature terminal effector prime cells.
The team discovered that this mechanism could be manipulated to maintain the terminal effector prime cells at this intermediate level, which would cause them to proliferate to create more numbers of memory T cells.
These findings highlight the possibility of targeting this pathway to boost protective immunity against both infections and tumors. We are extremely excited by these findings. By identifying this nutrient signaling axis, our studies provide new biological insights and therapeutic targets for enhancing memory T cell responses and protective immunity against pathogens and tumors.”
Hongbo Chi, PhD, Study First Author, Department of Immunology, St. Jude Children’s Research Hospital
Huang, H., et al. (2021) In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions. Cell. doi.org/10.1016/j.cell.2021.02.021.