Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses

Abstract

Cytokines and their receptors represent key targets for therapeutic intervention. Ligands are being used to supplement cell numbers that become depleted as a result of disease (organ failure, infection) or subsequent disease treatments (i.e. chemotherapy). Conversely, the inhibition of target cell binding by cytokines is an established strategy for abrogating pathologic cellular activities common to many immunological diseases. Considerable effort in biomedical research is being focused on the cytokine families that play a dominant role in regulating immunity and then prioritizing each member for its therapeutic potential. Currently, the interleukin-2 (IL-2) family of cytokines is widely recognized for its central involvement in controlling lymphocyte function and is the most explored for medical utility. Collectively, these proteins (or their antagonists) are either marketed drugs or have received advanced testing for an impressive array of indications including cancer, infectious disease, transplantation, inflammation and allergic asthma. Here we review the current understanding of IL-21, the most recent member of this cytokine family to be discovered. As will be discussed, IL-21 shares many of the same attributes as its relatives in that it has broad immunoregulatory activity and can modulate both humoral and cell-mediated responses. Its ability to stimulate durable anti-tumour responses in mice defines one therapeutic indication that merits clinical development.

Figure 1

IL-21 is a CD4⁺ T-helper cytokine. The expression of IL-21 following antigen-specific T-cell activation stimulates a number of predominant changes in an adaptive immune response. IL-21 has minimal effects on CD4⁺ T-cell proliferation and its regulation of Th1 versus Th2 differentiation needs further clarification. Its role in stimulating cell-mediated anti-tumour responses via enhancement of CD8⁺ T-cell and NK-cell differentiation is firmly established, as is its regulation of B-cell-mediated humoral immunity. Expression of IL-21R is low but detectable on monocytes and the affects of IL-21 on these cells remains to be established. IL-21R is also expressed on monocyte-derived dendritic cells where the inhibitory activity of IL-21 has been confirmed with immature dendritic cells but not activated dendritic cells.