Regulatory T Cells Proteins

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Regulatory T Cells Proteins

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Regulatory T Cells Proteins Background

Regulatory T cells as a suppressive cell

A long standing idea that a population of suppressive cells may contribute to peripheral tolerance gained acceptance in the mid 1980’s to mid-1990’s after a series of studies identified peripheral CD25+CD4 T cells as a sub-population of CD4 T cells that actively suppress the immune system and prevent the targeting of self or innocuous antigens. While this served as an important breakthrough in demonstrating the existence of a population of suppressive CD4 T cells, CD25 was an imperfect marker to use for studying the details of these cells, because CD25 can be expressed on a variety of different cell types, including effector T cells after activation.

Foxp3 mutations in both humans and mice can lead to multi-organ autoimmunity, the search for a more precise marker for the population of suppressive T cells resulted in a few different groups identifying Foxp3 as the key transcription factor that drives the development of these suppressor cells. By this time, these cells were generally regarded as a unique lineage of CD4 T cells called regulatory T cells (Tregs). Since their acceptance as a legitimate lineage of CD4 T cells, Tregs have been studied extensively.

Commitment to the Treg lineage can come about in the thymus or in the periphery. In both cases, expression of Foxp3 is necessary, although not fully sufficient to induce Treg commitment. As Tregs develop, they both begin to express Foxp3 and acquire a characteristic pattern of hypomethylation that favors expression of genes commonly expressed by Tregs. The methylation pattern can be passed onto daughter cells during mitosis, allowing for the stability of the Treg fate through cell proliferation. The precise cues that initiate commitment to the Treg lineage are not completely clear, but TCR stimulation is involved. Foxp3 expression is induced in the thymus in response to strong recognition of MHC plus peptide and the Treg specific hypomethylation pattern is induced following extended contact between the TCR and MHC plus peptide. In the periphery, TCR stimulation in a tolerogenic environment favors Treg differentiation and imprints Tregs that develop in the periphery with a unique methylation pattern. The result of this development is a population of Tregs that have wide array TCR specificities that recognize both self and foreign peptides. As a population, then, Tregs can use a variety of different mechanisms to suppress unwanted immune responses throughout the host against a huge variety of potential targets.

Precisely how Tregs suppress effector cells is still under investigation, but several key mechanisms are known. Within tissues, Tregs can produce the anti-inflammatory cytokine IL-10 to counteract the presence of pro-inflammatory cytokines such as IFNγ. Of particular importance within secondary lymphoid organs, Tregs also constitutively express CTLA-4. CTLA-4 is a surface protein that can bind to the costimulatory molecules CD80 and CD86 on the surface of antigen presenting cells (APCs) with very high affinity. CTLA-4 mediated binding to CD80 and CD86 can both block effector T cells from gaining access to co-stimulation and lead to the removal of the costimulatory molecules from the surface of the APC, leaving the APC less able to provide signal two to an effector T cell. The importance of CTLA-4 for Treg function has been demonstrated using a conditional knockout system. Mice in which Tregs alone are unable to express CTLA-4 develop fatal auto-immunity with many of the same symptoms that develop in mice that fully lack Tregs. Armed with these, and several more, mechanisms of suppression, mature Tregs respond to different risks by expressing various homing receptors so that they can migrate to where they are needed to maintain or restore homeostasis. Thus, while more is certain to be discovered, much is already known about what molecular tools Tregs use to localize to where they are needed and suppress unwanted immune response.


Regulatory T cells during infections

The appreciation that Tregs are always present and capable of suppressing unwanted immune responses was a major breakthrough in our understanding of how allergies and autoimmunity are prevented despite the presence of T cells and B cells that could initiate unwanted and damaging immune responses. However, the constant presence of Tregs also raises the question as to how Tregs allow, when appropriate, an immune response against a pathogen and what role they play throughout the subsequent immune response.

Some early studies suggested that Treg-mediated suppression can be overcome when dendritic cells (DCs) with a high enough level TLR stimulation present antigens to effector cells. Concurrently, however, other studies were demonstrating that Tregs expand in response to infection. This suggested that Tregs are not simply prevented from suppressing an anti-pathogen immune response by being switched off, but rather play a dynamic role in shaping how the immune response develops.

An early breakthrough study showed that an immune response against Leishmania major that develops without Tregs present is more robust than the immune response that develops when Tregs are present. Thus, the absence of Tregs allows for the clearance of the parasite. Interestingly, in this model, fully functioning immune memory depends on the persistence of antigen, so the sterilizing immunity that can be achieved when Treg activity is disrupted prevents the establishment of proper memory; so Treg-mediated parasite persistence ends up benefitting both the host and the parasite.

A similar, although less well-noted, study using a model of pneumonia induced by Pneumocystis carinii was published just before the study looking at L. major infection. P. carinii causes a persistent infection in mice that can lead to immune-mediated pneumonia. When chronically infected Rag-/- mice received a transfer of effector CD4 T cells, the pathogen load was decreased, but pneumonia was induced, presumably because of unrestrained activity of the effector CD4 T cells. In contrast, when chronically infected Rag -/- mice received a transfer of both effector CD4 T cells and Tregs, the parasite load was not significantly affected, but the mice were also largely protected from pneumonia, showing that Tregs play a key role in limiting the degree of immunopathology that is sustained during an immune response.

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