mechanism of retrovirus-induced leukaemia illuminated by tocky

Our new review/opinion paper proposes a new paradigm for understanding self-reactive T cells, highlighting their spectrum and significant roles in T cell response and infections caused by the leukemia-inducing Human T-cell Leukemia Type 1 virus (HTLV-1) (Ono & Satou, 2024).

The Spectrum Self-reactive T cells Elucidated by Tocky

The Nr4a3-Tocky technology plays a key role in elucidating the role of a newly defined type of T-cells, Periodic TCR-Signalled T-Cells. These cells include regulatory T-cells (Treg) and memory-phenotype T-cells, both of which receive T-cell receptor (TCR) signalling spontaneously and periodically.

This type of TCR signalling contrasts with the acute TCR signals typically observed during inflammatory responses. This innovative technology facilitates the understanding that these T cells have TCRs that react to antigens in the body, often categorised as self-reactive.

Importantly, some Treg cells may lose their Foxp3 expression and participate in the memory-phenotype T cell group. Meanwhile, memory-phenotype T cells may newly activate Foxp3 transcription, thus joining the Treg fraction.

Ultimately, the distinction between the two populations hinges on Foxp3 expression. This leads us to a straightforward understanding that Foxp3 expression is dynamically regulated within the reactive T-cell repertoires. This regulation allows the investigation of self-reactive T cells as a spectrum of T cells, in which T cells show dynamic changes over time.

These findings support that the periodic TCR signals are the unique dynamics that characterise these self-reactive T cells and related cells.

Self-Reactive T Cells’ Response: Periodical and Acute Signals

Regardless of their self-reactivity, T cells can respond to antigen stimulation. However, self-reactive T cells, periodically receiving TCR signals, may respond uniquely to acute TCR signals.

Various publications have discussed this topic for Treg and memory-phenotype T cells. Below is a summary figure illustrating possible behaviours of self-reactive T cells.

HTLV-1 infection

Our analysis collectively supports the model that HTLV-1 preferentially infects and transforms self-reactive T cells, which periodically receive TCR signalling, exploiting activation mechanisms within these T cells.

Some researchers claimed that ‘HTLV-1 induces tumorigenesis in regulatory T cells,’ but our investigation has clarified that their perspective is overly simplistic and fails to capture the fundamental aspects of processses during infection and transformation.

In my next article, I will explore how this mechanism has been investigated in various studies, highlighting an underappreciated role of HTLV-1 research in the discovery of CD25+CD4+ T cells – regulatory T cells – and thereby highligh the missing piece in the understanding of these cells.

Despite extensive regulatory T cell (Treg) research, fundamental questions on in vivo dynamics remain to be answered. The current study aims to dissect several interwoven concepts in Treg biology, highlighting the ‘self-reactivity’ of Treg and their counterparts, namely naturally-arising memory-phenotype T-cells, as a key mechanism to be exploited by a human retroviral infection. We propose the novel key concept, Periodic T cell receptor (TCR)-signalled T-cells, capturing self-reactivity in a quantifiable manner using the Nr4a3-Timer-of-cell-kinetics-and-activity (Tocky) technology. Periodic and brief TCR signals in self-reactive T-cells contrast with acute TCR signals during inflammation. Thus, we propose a new two-axis model for T-cell activation by the two types of TCR signals or antigen recognition, elucidating how Foxp3 expression and acute TCR signals actively regulate Periodic TCR-signalled T-cells. Next, we highlight an underappreciated branch of immunological research on Human T-cell Leukemia Virus type 1 (HTLV-1) that precedes Treg studies, illuminating the missing link between the viral infection, CD25, and Foxp3. Based on evidence by single-cell analysis, we show how the viral infection exploits the regulatory mechanisms for T-cell activation and suggests a potential role of periodic TCR signalling in infection and malignant transformation. In conclusion, the new perspectives and models in this study provide a working framework for investigating Treg within the self-reactive T-cell spectrum, expected to advance understanding of HTLV-1 infection, cancer, and immunotherapy strategies for these conditions.

The Spectrum Self-reactive T cells Elucidated by Tocky

Self-Reactive T Cells’ Response: Periodical and Acute Signals

HTLV-1 infection

References

2024