REGULATORY CELLS AND THE IMMUNE RESPONSE
T lymphocytes can specifically downregulate B-cell responses. This concept was demonstrated by experiments performed in mice immunized with keyhole limpet hemocyanin (KLH). If mice are primed and later boosted with KLH, a population of T lymphocytes can be isolated 2 weeks after the boost that markedly suppress the IgG anti-DNP response of genetically identical mice primed with DNP-KLH. However, this T-cell population will not suppress anti-DNP antibody production in animals immunized with DNP conjugated with a different carrier, such as bovine gammaglobulin (BGG). Other studies in mice have confirmed the existence of antigen-specific T cells that downregulate the activity of other T-cell subpopulations. Suppression appears to be a negative feedback exerted by activated regulatory T lymphocytes on other T lymphocytes. This negative feedback results in the inability of effector lymphocytes to respond adequately to stimulation.
In most experimental systems, regulatory activity is carried out by a subset of CD8+ lym-phocytes (known as suppressor T cells), but a role for regulatory CD4+ lymphocytes has also been demonstrated.
The mechanism of suppression by regulatory T lymphocytes remains uncertain. Two main possibilities have been considered:
1. Cross-regulation of T helper subsets may explain nonspecific suppression. Strongly activated TH1 cells may release soluble factors (such as interferon-γ ) that inhibit TH 2 activity and, consequently, interfere with B-cell activation. Con-versely, TH 2-produced IL-4 and IL-10 suppress TH1 responses by downregulat-ing IL-12 synthesis. Other cytokines, such as transforming growth factor (TGF-β ), which inhibits T-lymphocyte proliferation by blocking IL-2 transcrip- tion, and macrophage inflammatory proteins (e.g., MIP-1α ) may also play a role in the downregulation of immune responses.
2. Direct cell-to-cell signaling between regulatory cells and antigen-stimulated cells may be the key factor when the downregulation affects a specific immune response. For example, upregulation of CTLA-4 is known to result in the deliv-ery of downregulatory signals, including the synthesis and release of TGF-β . However, our knowledge about downregulatory interactions and their control is extremely sketchy.