Following an immune cell's career path

July 6, 2012, RIKEN
Figure 1: The various classes of T cells are capable of responding to pathogenic threats and restraining the resulting immune response to avoid inflicting damage on host tissues. Credit: Dr Triche, National Cancer Institute, USA

The immune system produces diverse varieties of T cells (Fig. 1), such as pathogen-destroying cytotoxic T cells and immune response-boosting helper T cells. Regulatory T (Treg) cells restrain these other cells and prevent the body from overreacting to threats or generating a dangerous autoimmune response.

Treg are usually identified by expression of the transcriptional regulator protein Foxp3, but new work from a team led by Shohei Hori of the RIKEN Research Center for Allergy and Immunology in Yokohama has demonstrated that this is not a reliable signature. 

Several groups have obtained data suggesting that Treg cells can essentially ‘change careers’, losing their Foxp3 expression and transforming into other T cell types. However, findings from Hori and colleagues led them to propose an alternative ‘heterogeneity model’. “Our observations suggested that these phenomena can be fully explained by a minor ‘uncommitted’ population of Foxp3+ T cells without assuming reprogramming,” he says. His group has now provided compelling evidence for this hypothesis by using a labeling technique that allowed them to distinguish cells currently expressing Foxp3 from those that are not, but which have expressed this protein in the past.

The researchers identified two groups of Foxp3-expressing cells that responded differently to an immune stimulus. Most expressed this protein stably and at high levels, and exhibited the functional characteristics of Treg cells. A minority fraction displayed transient bursts of Foxp3 expression, but ultimately developed into other T cell types. These ‘exFoxp3’ cells did not appear to represent reprogrammed Treg cells, but rather a separate pool of T cells that only produce this protein sporadically. 

Interestingly, his team also learned that some Treg cells do enter a state where they stop expressing Foxp3, although they retain ‘memory’ of their identity as Treg cells. This is achieved via chemical modifications to the DNA within the gene encoding Foxp3, and immune stimulation promptly leads to robust re-expression of this . “This should force people to reconsider the popular but oversimplified view of Foxp3 as the master regulator of Treg cells,” says Hori. 

The events that determine this expression profile are therefore likely to prove more important in establishing cellular identity than the presence or absence of Foxp3. “It has been speculated that the Treg lineage is determined by a higher-order regulatory pathway upstream of Foxp3, but the nature of this system is unknown,” says Hori. In future work, he plans to partner with colleagues at other RIKEN laboratories to investigate this question more closely.

Explore further: New insight into immune tolerance furthers understanding of autoimmune disease

More information: Miyao, T., et al. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262–275 (2012).

Komatsu, N., et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proceedings of the National Academy of Sciences 106, 1903–1908 (2009).

Related Stories

New insight into immune tolerance furthers understanding of autoimmune disease

September 15, 2011
It is no easy task to preserve the delicate balance that allows us to maintain a strong immune system that can defend us from harmful pathogens, but that is sensitive enough to correctly identify and spare our own cells. ...

Ensuring the persistence of immune memory

September 16, 2011
Structures within the lymph nodes known as germinal centers (GCs) help the body to maintain long-term immune defense against foreign threats. The GCs essentially act as sites where antibody-producing B cells undergo a process ...

Recommended for you

Genomics reveals key macrophages' involvement in systemic sclerosis

January 18, 2018
A new international study has made an important discovery about the key role of macrophages, a type of immune cell, in systemic sclerosis (SSc), a chronic autoimmune disease which currently has no cure.

First vaccine developed against grass pollen allergy

January 18, 2018
Around 400 million people worldwide suffer in some form or other from a grass pollen allergy (rhinitis), with the usual symptoms of runny nose, cough and severe breathing problems. In collaboration with the Viennese firm ...

Researchers discover key driver of atopic dermatitis

January 17, 2018
Severe eczema, also known as atopic dermatitis, is a chronic inflammatory skin condition that is driven by an allergic reaction. In their latest study, researchers at La Jolla Institute reveal an important player that promotes ...

Who might benefit from immunotherapy? New study suggests possible marker

January 16, 2018
While immunotherapy has made a big impact on cancer treatment, the fact remains that only about a quarter of patients respond to these treatments.

Researchers identify new way to unmask melanoma cells to the immune system

January 16, 2018
system, which enables these deadly skin cancers to grow and spread.

How the immune system's key organ regenerates itself

January 15, 2018
With advances in cancer immunotherapy splashing across headlines, the immune system's powerful cancer assassins—T cells—have become dinner-table conversation. But hiding in plain sight behind that "T" is the organ from ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.