Costimulatory signals controlling regulatory T cells
- Division of Immunology and Rheumatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5166
The concept of specialized suppressor T cells (now commonly called regulatory T cells or Tregs), which was abandoned by most immunologists in the early 1980s (1), was rescued by the description of a marker for their identification and isolation by Sakaguchi et al. (2), who, in 1995, described a CD4+CD25+ subpopulation of T cells that could prevent pathology in a mouse autoimmune disease model. However, the marker CD25, the α-chain of the high-affinity IL-2 receptor, is also induced on conventional T cells after activation. The dilemma arose as to how one could distinguish genuine Tregs from recently activated conventional T cells. Furthermore, the suppressor activity of CD4+CD25+ Tregs in vitro depended on their prior stimulation and could be overcome by strong costimulation (3, 4). What were the signals that controlled the activity of CD4+CD25+ Tregs in vivo that allowed them to inhibit certain immune responses but not others?
Glucocorticoid-Induced Tumor Necrosis Factor Receptor (GITR) and GITR Ligand (GITRL)
In a recent issue of PNAS, Tone et al. (5) reported the cloning of the murine ligand for GITR, a tumor necrosis factor receptor superfamily member that had previously been demonstrated to regulate CD4+CD25+ Treg function. Searching for novel Treg markers, two groups had independently found that freshly isolated CD4+CD25+ Treg cells but not conventional CD4+CD25– T cells expressed uniformly high levels of GITR (6, 7). Activation of the CD4+CD25– T cells in vitro rapidly increased GITR surface expression to levels comparable to that on CD4+CD25+ Tregs. GITR thus was no better than CD25 in distinguishing Tregs from activated conventional T cells. However, the addition of anti-GITR antibodies to the coculture of CD4+CD25– and CD4+CD25+ T cells in vitro …
