Transmembrane Signals Mediated by IL-2 and IL-15 Control the Life and Death of Lymphocytes

Abstract

Immune responses are regulated by a series of cytokines that exhibit a high degree of redundancy and pleiotropy controlling a wide range of functions in various cell types. This redundancy is explained in part by the sharing of common receptor subunits among members of the cytokine receptor family. Each cytokine utilizes its own private receptor subunit but may also share public receptor subunits with other cytokines. This sharing of subunits is exemplified by the receptors within the common gamma (γc) receptor system. The γc is an essential element of the multisubunit receptors for IL-4, IL-7, IL-9, IL-21 as well as for the two cytokines, the focus of this chapter, IL-2 and IL-15 (Takeshita et al. 1992; Kondo et al. 1993; Noguchi et al. 1993; Leonard 2000). The shared actions of IL-2 and IL15 on T and natural killer (NK) cells also require the expression of IL-2/15Rβ as well as the private alpha chains IL-2Rα and IL-15Rα used by IL-2 and IL-15 respectively (Sharon et al. 1986; Tsudo et al. 1986; Bamford et al. 1994; Giri et al. 1994, 1995; Grabstein et al. 1994). When this receptor constellation is utilized, IL2 and IL-15 activate similar JAK1 and JAK3 (Janus kinases) as well as STAT5 (signal transducers and transactivators of transcription)-dependent signaling pathways (Witthuhn et al. 1994; Johnston et al. 1995; Lin et al. 1995). As might be anticipated from this sharing of receptor subunits and the use of common elements in one signaling pathway, there is a significant overlap between the immunological functions of IL-2 and IL-15 (Waldmann and Tagaya 1999). Both cytokines stimulate the proliferation of different subsets of activated T cells involved in the maintenance of NK cells and act as co-stimulatory molecules for B cell immunoglobulin synthesis (Waldmann and Tagaya 1999). In addition to shared functions, IL-2 and IL-15 provide distinct and at times contrasting contributions to T cell-mediated immunity (Waldmann et al. 2001). IL-2 plays a central role in activation-induced cell death (AICD) and thereby is involved in peripheral tolerance to self. In contrast, the transgenic expression of IL-15 in mice inhibits IL-2-mediated AICD (Marks-Konczalik et al. 2000). Furthermore, IL-15 stimulates the persistence of CD8+ memory phenotype cells whereas IL-2 inhibits their survival (Zhang et al. 1998; Marks-Konczalik et al. 2000; Ku et al. 2000; Waldmann et al. 2001). The many biophysical elements involved in the relationships among receptor subunits as well as the transmembrane signals mediated by IL-2 and IL15 that control the life and death of lymphocytes are the subjects of this chapter. Transmembrane Signals Mediated by IL-2 and IL-15 Control the Life and Death of Lymphocytes