Study uncovers how CD8+ T cells can divide and produce two distinct daughter cells

An immunological problem has been addressed by scientists at St. Jude Children’s Research Hospital. Despite being genetically identical, a CD8+ T cell can divide and produce two functionally different daughter cells. The researchers have revealed one technique through which the immune system provides instant and long-term protection. The results were published in the journal Molecular Cell.

Study uncovers how CD8+ T cells can divide and produce two distinct daughter cells
Cliff Guy, PhD, director of lab operations, Immunologic Imaging; and Swantje Liedemann, PhD, postdoctoral research associate, St. Jude Immunology. Image Credit: St. Jude Children’s Research Hospital.

The researchers demonstrated how a particular protein complex directs the translation of a key immune transcription factor in a parent T cell’s region. Because the transcription factor is only in one location, it is inherited asymmetrically into two daughter cells when the cell divides. The transcription factor causes one daughter cell to express a set of genes, causing it to become an effector cell, while another becomes a memory cell.

Our results hint that events that happen very early in a T cell’s life can influence the function of the cell much later. We have uncovered one way in which the immune system ensures that when T cells are activated, the response will be diverse, with some cells, the effectors, launching a rapid assault on the invader and others hanging back in reserve for later, as memory cells.”

Doug Green, PhD, Study Corresponding Author, Department of Immunology Chair, St. Jude Children’s Research Hospital

Two very different daughters with the same DNA

Many distinct cell types with various roles make up the immune system. CD8+ T cells are one of the most common cell types. These cells are in charge of destroying infected and tumor cells directly. A particular cell activates them by presenting a piece of virus or tumor cell, known as an antigen, on their surface. The immunological synapse is the site of interaction between T cells and antigen-presenting cells. T cells divide into genetically similar daughter cells after activation.

Many daughter cells develop into effector cells, which destroy contaminated or cancerous cells. Some of the daughter cells, on the other hand, develop memory cells that help defend against future infections or cancer. It was previously unknown how both effector and memory cells might originate from the same parent T cell until this study.

An unstable protein, lost without translation

Green’s team had previously demonstrated that the amounts of the protein c-Myc in the first two daughter cells of an activated T-cell parent varied. This is significant because c-Myc is a transcription factor that regulates the production of genes that cause T cells to transform into effector cells.

However, c-Myc is unstable, and within 20 minutes, half of the c-Myc in the cell has vanished. So, how does c-Myc stay in the appropriate place for long enough to be preferentially split into one daughter cell?

In most cases, the answer is mRNA. mRNA acts as a template for cells to employ in the production of proteins. Because its mRNA template is constrained to one area, an unstable protein concentrates in one portion of the cell. c-myc mRNA transcripts, on the other hand, appeared to be distributed equally throughout the cell.

The protein complex that produces c-Myc, on the other hand, was exclusively found near the immunological synapse, according to the researchers. The eukaryotic translation initiation factor 4F (eIF4F) complex is the one responsible for translating c-Myc. The eIF4F complex is a translation machinery that converts mRNA instructions into proteins, such as c-Myc in this case.

On one end, the c-myc mRNA has a complex structure. Only the eIF4F complex can utilize the c-myc mRNA’s intricate structure to begin the protein translation process. As a result, c-Myc is exclusively created in the presence of eIF4F, relegating c-Myc to one side of the cell.

This is the first time the location of translation machinery has been identified as a factor in why a protein is only found in one area of the cell.

Finding a molecular platform

While eIF4F's position explains why c-Myc is only found in one portion of the cell, it also raises a new question: how did eIF4F get concentrated on one end of the cell?

The researchers employed a method called expansion microscopy to “blow up” a T cell to determine how eIF4F traveled through it. This is about similar to blowing up a mouse to elephant proportions.

The approach was employed for the first time using a primary T cell in this investigation. Green’s team looked at both trafficking pathways and eIF4F’s final installation on a molecular “platform” linked with the immune synapse as eIF4F traveled through the cell to one end via the immune synapse.

Genetic “bar coding” confirms the fate of sister cells

Green's team confirmed that pairs of “sister” cells—daughter cells from the same parent—began to express genes from two distinct lineages, effector and memory. To determine whether individual cells were directly connected, the scientists used a genetic “bar code” technique.

Outside of the transposed bar code sequence, many cells were genetically similar, hence this was a difficult technological achievement. However, the researchers were able to sequence the cells’ mRNA transcripts. The transcripts revealed that genetically identical sister cells with identical barcodes expressed distinct genes associated with their T-cell subtype.

This study is the first time that we could say, with confidence, that two sister cells can have very different gene expression patterns. The study also demonstrates that there are basic principles of cellular architecture, which create platforms on which intracellular events can localize. Upon division, asymmetries in the distribution of these platforms can result in diversification of cell fate. The details may not be the same for other cell types, but the principles are likely to hold."

Doug Green, PhD, Study Corresponding Author, Department of Immunology Chair, St. Jude Children’s Research Hospital

Source:
Journal reference:

Liedmann, S., et al. (2022) Localization of a TORC1-eIF4F translation complex during CD8+ T cell activation drives divergent cell fate. Molecular Cell. doi.org/10.1016/j.molcel.2022.04.016.

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