Regulatory T Cells
For many years, different laboratories — usually using different protocols — have found evidence of lymphocytes that suppress immune responses: antibody-mediated and/or cell-mediated. But these cells have been difficult to study, primarily because of the difficulty is isolating clones; that is, populations descended from a single cell.
Originally called suppressor T cells (Ts cells), the most promising recent candidates are now called regulatory T cells (Treg).
Most CD4+ T cells belong to one or another of the helper T cell subsets [Link to discussion]. However ~10% of them do not. These so-called T-regulatory (Treg) cells
- express a transmembrane protein (called CD25) that is the alpha chain of the receptor for interleukin-2 (IL-2);
- express a transcription factor called Foxp3 that alters the expression of many genes — enhancing some; suppressing others;
- express a cell-surface protein designated CTLA-4 ("cytotoxic T-lymphocyte-associated antigen 4").
- Like other T cells, they also express the alpha-beta T-cell receptor for antigen (αβ TCR) and can only be activated if
- However, if activated, they begin to secrete large amounts of interleukin 10 (IL-10) and TGF-β.
- These lymphokines are powerful immunosuppressants and may be one of the mechanisms by which Treg cells inhibit
- Treg cells may also kill the various kinds of effector T cells by binding to them and secreting granzymes and perforins.
- But perhaps the most important suppressor mechanism is the effect of Treg cells on antigen-presenting cells (APCs) like dendritic cells. The CTLA-4 molecules on Treg cells bind tightly to the B7 molecules on the APCs, strip them off the APC, engulf them by endocytosis and destroy them. Having lost their B7 (CD80 and 86) molecules, the APCs can no longer present "signal 2" to activate effector T cells.
Treg cells respond to the presence of interleukin-2 (IL-2) by rapid proliferation [Link]. Because IL-2 is secreted by effector T cells, this provides a negative-feedback mechanism: inflammatory T-cell activity (e.g., by Th1 cells) is restrained by the resulting expansion of Treg cells.
There are two sources of Treg cells in the body:
- Some are generated in the thymus early in life. These are called thymic Treg cells, tTreg, (also natural Treg cells or nTreg);
- Others are generated in various tissues of the body throughout life. These are called peripheral Treg cells, pTreg, (also induced Treg cells or iTreg).
Many of the antigenic peptides recognized by the TCRs of tTreg cells are self-peptides and probably a major function of these cells is to inhibit other T cells from mounting an immune attack against self components; that is, to protect the body against autoimmunity.
This idea receives support from these observations:
- Destruction of their tTreg cell population causes mice to spontaneously develop a spectrum of autoimmune diseases.
- Nude mice (which have no T cells of their own — link to discussion) develop autoimmune disease if they are given CD4+ T cells that have been depleted of the CD25+ population; that is, lack Treg cells.
- Both humans and mice with disabling mutations in their genes encoding Foxp3 suffer devastating autoimmune disorders.
Autoimmunity is a failure of self tolerance. Link to a discussion of tolerance.
- On the other hand, mice deficient in Treg activity attack tumor cells far better than normal mice. [More]
Peripheral Treg cells develop from CD4+ T cells that, after binding antigen with their TCR, have been stimulated by TGF-β and retinoic acid [Link]. pTreg cells are abundant at mucosal surfaces that separate the external from the internal environment:
- Lungs. Here they are exposed to inhaled antigens and can dampen the response to potential allergens that could precipitate an attack of asthma.
- Intestine. Here they are exposed to ingested antigens and can make the animal tolerant to the many antigens that are part of its diet. It has long been known that eating antigenic material can induce a condition of "oral tolerance". pTreg cells secrete large amounts of IL-10 as well as of transforming growth factor-beta (TGF-β). Mice that cannot make enough IL-10 develop inflammation of the large intestine, and giving IL-10 to them cures it.
- Placenta. pTreg cells are abundant in the placenta and are one of several factors that suppress any attempt by the mother's immune system to reject her fetus (with its foreign histocompatibility antigens contributed by the father). [More]
Further research will be needed to sort out the relationships between these and other T cells that suppress immune responses. This work will be important because it could lead to improvements in
- suppressing the rejection of organ transplants;
- treating patients with autoimmune disorders like Type 1 diabetes mellitus;
- treating graft-versus-host disease (GVHD).
Clinical trials of Treg cells are underway for all these conditions.
14 May 2013