Different forms of severe combined immunodeficiency (SCID) diseases occur as a result of inactivating mutations in multifunctional immune system regulators. These mutations lead to developmental or functional defects in T lymphocytes, which can also be accompanied by variable defects in B lymphocytes and/or natural killer cells. The most common form of SCID, X-linked SCID (XSCID), is caused by mutations in the common cytokine receptor gamma-chain. The gamma-chain subunit is an essential component of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor complexes, indicating that signaling by one or more of these cytokines is required for normal immune system development. Multiple studies have now demonstrated that cytokines belonging to the gamma-chain family serve as critical regulators of the development, survival, proliferation, differentiation, and/or function of cells of both the innate and adaptive immune systems. The unique and overlapping effects of these cytokines on different immune cell types are summarized here.
Cytokines belonging to the common cytokine receptor gamma-chain family include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Members of this family signal through receptor complexes that contain the gamma-chain/IL-2 R gamma subunit. The gamma-chain subunit associates with different cytokine-specific receptor subunits to form unique heterodimeric receptors for IL-4, IL-7, IL-9, and IL-21, or associates with both IL-2/IL-15 R beta and IL-2 R alpha or IL-15 R alpha to form heterotrimeric receptors for IL-2 or IL-15, respectively. Common gamma-chain family cytokines generally activate three major signaling pathways that promote cellular survival and proliferation, the PI 3-K-Akt pathway, the RAS-MAPK pathway, and the JAK-STAT pathway. Differences in the expression patterns of the cytokines or their unique receptor components, along with the activation of different STAT proteins may account for some of the distinct effects mediated by gamma-chain family cytokines.
Signaling by gamma-chain family cytokines plays a major role in regulating the development, survival, proliferation, differentiation and/or function of cells of the immune system. The importance of the gamma-chain family cytokines for the establishment and maintenance of the immune system is emphasized by the fact that mutations in common gamma-chain/IL-2 R gamma in humans are associated with a disease known as X-linked severe combined immunodeficiency (XSCID), which is characterized by the absence of T cells and natural killer (NK) cells, and the presence of non-functional B cells. Knockout studies in mice have demonstrated that the lack of T cell and NK cell development in this disease can be primarily attributed to the respective loss of IL-7 and IL-15 signaling, while the loss of both IL-4 and IL-21 signaling leads to defective B cell function. Similar studies revealed that in contrast to humans, B cell development in mice also requires IL-7 signaling. Several additional unique and overlapping effects of the common gamma-chain family cytokines on different immune cell types have been documented. A number of these effects are highlighted here to demonstrate the central role that common gamma-chain family cytokines play in controlling immune system functions. Understanding the mechanisms by which these cytokines act and how their signaling pathways can be regulated may have therapeutic implications not only for a variety of immunodeficient disease states, but also for disorders resulting from aberrant or exaggerated immune system activation.