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.

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 T_reg cells due to a lack of IL-2 from CD4⁺CD25⁻ T cells in the periphery. Adoptive transfer of T_reg cells into IL-2^−/− mice leads to unrecoverable levels of T_reg. B, CD25^−/− mice also develop fatal lymphoproliferative disease as a result of a paucity of naturally occurring T_reg 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 T_reg cells into CD25^−/−mice leads to recoverable levels of T_reg 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⁺ T_reg cells (which are IL-2^−/− in phenotype) in the periphery due to IL-2 being provided by CD25^−/− T_helper cells. CD25^−/− T cells destined to be T_reg cells die. Subsequently, IL-2^−/− T_reg cells suppress both IL-2^−/− and CD25^−/− T_helper cells through an as-yet-undefined mechanism.

FIGURE 2

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

FIGURE 3

IL-2 maintains self-tolerance through T_reg cells. A yin/yang type relationship exists between T_helper cells and T_reg cells in vivo. T_helper cells provide IL-2 that is critical for the survival and function of naturally occurring T_reg cells in vivo. T_reg cells suppress autoreactive or foreign reactive T_helper cells, depending on the situation. If either one does not exist, an imbalance ensues. Autoimmunity develops if T_reg cells are absent or T_reg cells lose IL-2R and eventually die without IL-2 support when T_helper 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⁺ T_reg cells (red) suppress CD4⁺ T_helper cells (green), CD8⁺ T cells (blue), and dendritic cells (pale red). CCR4⁺ T_reg 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 T_reg 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 T_reg 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.