CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2

Abstract

CD4+CD25+ T regulatory (Treg) cells control immunologic tolerance to self-antigens and play a role in suppressing antitumor immune responses, but the mechanism of suppression in vivo remains uncertain. Recently, signaling through the high-affinity interleukin-2 (IL-2) receptor has been shown to be critical for Treg cell differentiation and survival in vivo. Mice deficient in IL-2 or its receptor (CD25 or CD122) or deficient in downstream signaling molecules, including JAK-3 and STAT-5, do not develop a stable population of Treg cells and subsequently acquire lymphoproliferative disease and autoimmunity. in vitro, IL-2 is required to expand Treg cells and to induce their suppressive characteristics. Conversely, IL-2-based regimens can activate cellular antitumor immunity and are the mainstay of immunotherapies directed against melanoma and kidney cancers. Given the seemingly disparate effects of IL-2, the authors discuss the possibility that IL-2 may not be the optimal T-cell growth factor in vivo, but rather an inducer of self-tolerance. The authors propose that other gamma c-signaling cytokines, including IL-15, may be alternative choices for the immunotherapy of cancer.

Figures

FIGURE 1

Phenotype of IL-2−/− mice, CD25−/− mice, and mixed bone marrow chimeras. A, IL-2−/− mice develop fatal lymphoproliferative disease as a result of a paucity of naturally occurring Treg cells due to a lack of IL-2 from CD4+CD25− T cells in the periphery. Adoptive transfer of Treg cells into IL-2−/− mice leads to unrecoverable levels of Treg. B, CD25−/− mice also develop fatal lymphoproliferative disease as a result of a paucity of naturally occurring Treg cells in the periphery, which is due to the lack of IL-2 signaling either in the thymus or the periphery. However, adoptive transfer of Treg cells into CD25−/−mice leads to recoverable levels of Treg cells, presumably because CD25−/− T cells can still make IL-2. C, Two wrongs make a right: mixed bone marrow chimeras of IL-2−/− and CD25−/− bone marrow lead to a stable engraftment of CD4+CD25+ Treg cells (which are IL-2−/− in phenotype) in the periphery due to IL-2 being provided by CD25−/− Thelper cells. CD25−/− T cells destined to be Treg cells die. Subsequently, IL-2−/− Treg cells suppress both IL-2−/− and CD25−/− Thelper cells through an as-yet-undefined mechanism.

FIGURE 2

Thelper cells provide IL-2 to Treg cells in the periphery. A, Treg cells suppress CD4+ and CD8+ T cells and dendritic cells in the periphery through undefined mechanisms. B, Treg cells may compete for IL-2 as a growth factor. Thelper cells provide IL-2 that has a 100-fold higher affinity for its trimeric receptor on Treg cells than its dimeric form on T-helper cells. C, Affinities (kd) of IL-2 receptor complexes for IL-2.

FIGURE 3

IL-2 maintains self-tolerance through Treg cells. A yin/yang type relationship exists between Thelper cells and Treg cells in vivo. Thelper cells provide IL-2 that is critical for the survival and function of naturally occurring Treg cells in vivo. Treg cells suppress autoreactive or foreign reactive Thelper cells, depending on the situation. If either one does not exist, an imbalance ensues. Autoimmunity develops if Treg cells are absent or Treg cells lose IL-2R and eventually die without IL-2 support when Thelper cells are absent.

FIGURE 4

Status of the immune system during normal homeostasis, IL-2 therapy, or nonmyeloablative conditioning. A, During normal homeostasis, CD4+CD25+ Treg cells (red) suppress CD4+ Thelper cells (green), CD8+ T cells (blue), and dendritic cells (pale red). CCR4+ Treg cells are recruited to the tumor by chemokines, such as CCL22, and may suppress tumor-reactive T cells through TGF-β, IL-10, or other undefined mechanisms such as IL-2 deprivation, cell–cell contact, and so forth. B, Exogenous IL-2 therapy may expand Treg cells, although it helps initially in a few patients (some tumor destruction). C, Nonmyeloablative conditioning (lymphodepletion) with cyclophosphamide and fludarabine depletes all endogenous T cells, including Treg cells, and allows transferred tumor-reactive T cells (TILs) to be activated and kill tumor. Access by tumor-reactive T cells to homeostatic cytokines such as IL-7 and IL-15 in addition to exogenous IL-2 is improved and enhances CTL activity against tumor.