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 either the Th1 or Th2 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 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 (CD80 and CD86) on the antigen-presenting cell. [More]
- However, if activated, they begin to secrete large amounts of interleukin 10 (IL-10).
- This lymphokine is a powerful immunosuppressant and may be one of the mechanisms by which Treg cells inhibit
- The CTLA-4 molecules on Treg cells bind very tightly to the B7 molecules on antigen-presenting cells and interfere with the ability of effector T cells (Th1, Th2, CTL) to receive the "second signal" they need to go to work — another, probably crucial, mechanism of immune suppression.
- The antigenic peptides recognized by their TCRs tend to be self-peptides and perhaps the 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 large amounts of CD25 on their surface.
- 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, but unlike Tr1 cells, their main lymphokine is TGF-β.
- Also 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
19 October 2008