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 have been given other names. We shall look at three examples:
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
- it binds to the peptide-class II MHC molecule for which it is specific. [Link to discussion] and
- the cell also receives costimulation from B7 molecules (also known as CD80 and CD86) on the antigen-presenting cell. [More]
- 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.
The antigenic peptides recognized by the TCRs of Treg cells tend to be self-peptides and probably a major function of Treg 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 Treg 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.
- On the other hand, mice deficient in Treg activity attack tumor cells far better than normal mice. [More]
- Tr1 cells resemble Treg cells in several ways, although they do not express Foxp3 nor large amounts of CD25.
- They require IL-10 for their formation and, once mature, secrete large amounts of it as well as of transforming growth factor-beta (TGF-β).
- Tr1 cells are abundant in the intestine, and their chief function may be to make the animal tolerant to the many antigens that are part of its diet.
- This idea is supported by the observation that mice that cannot make enough IL-10 develop inflammation of the large intestine, and giving IL-10 to them cures it.
- Th3 cells are also prevalent in the intestine. Their main lymphokine is TGF-β.
- Like Tr1 cells, they suppress immune responses to ingested antigens. It has long been known that eating antigenic material can induce a condition of "oral tolerance". Th3 and/or Tr1 cells may be the responsible agents.
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
Clinical trials of Treg cells are underway for all these conditions.
6 June 2011