Regulatory Cells and the Immune Response

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.

A. The Nature of Regulatory Cells

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.

B. Mechanism of Suppression

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.