Human CD4⁺ central and effector memory T cells produce IL-21: Effect on cytokine-driven proliferation of CD4⁺ T cell subsets

IL-21 regulates certain functions of T cells, B cells, NK cells and dendritic cells. Although activated CD4⁺ T cells produce IL-21, data identifying the specific CD4⁺ T cell subsets that produce IL-21 are conflicting. In a previous study, mouse IL-21 message was detected in T_H2, whereas human IL-21 (hIL-21) message was found in both T_H1 and follicular helper T cells. To identify the IL-21-secreting cell populations in human, we established a hybridoma cell line producing an anti-hIL-21 mAb. Intracellular hIL-21-staining experiments showed that hIL-21 was mainly expressed in activated CD4⁺ central memory T cells and in activated CD4⁺ effector memory T cells, but not in activated CD4⁺ naive T cells. Moreover, IL-21 was produced upon activation by some IFN-γ-producing T_H1-polarized cells and some IL-17-producing T_H17-polarized cells, but not by IL-4-producing T_H2-polarized cells. These results suggest that specific CD4⁺ T cell populations produce IL-21. In the functional analysis, we found that IL-21 significantly enhanced the cytokine-driven proliferation of CD4⁺ helper T cells synergistically with IL-7 and IL-15 without T cell activation stimuli. Taken together, IL-21 produced from CD4⁺ memory T cells may have a supportive role in the maintenance of CD4⁺ T cell subsets.