Survey Interleukin-7: physiological roles and mechanisms of action R. Hofmeister a , A.R. Khaled a , N. Benbernou b , E. Rajnavolgyi a , K. Muegge b , S.K. Durum a, * a Laboratory of Molecular Immunoregulation, NCI, USA b SAIC, Frederick, MD 21702±1201, USA Abstract Interleukin-7 (IL-7), a product of stromal cells, provides critical signals to lymphoid cells at early stages in their development. Two types of cellular responses to IL-7 have been identi®ed in lymphoid progenitors: (1) a trophic eect and (2) an eect supporting V(D)J recombination. The IL-7 receptor is comprised of two chains, IL-7Ra and g c . Following receptor crosslinking, rapid activation of several classes of kinases occurs, including members of the Janus and Src families and PI3-kinase. A number of transcription factors are subsequently activated including STATs, c-myc, NFAT and AP-1. However, it remains to be determined which, if any, previously identi®ed pathway leads to the trophic or V(D)J endpoints. The trophic response to IL-7 involves protecting lymphoid progenitors from a death process that resembles apoptosis. This protection is partly mediated by IL-7 induction of Bcl-2, however other IL-7-induced events are probably also involved in the trophic response. The V(D)J response to IL-7 is partly mediated through increased production of Rag proteins (which cleave the target locus) and partly by increasing the accessibility of a target locus to cleavage through chromatin remodeling. Published by Elsevier Science Ltd. Keywords: Interleukin-7; Interleukin-7 receptor; Signal transduction; Apoptosis; V(D)J-recombination 1. Introduction Interleukin-7 (IL-7) is a cytokine that performs criti- cal functions during lymphoid development. In this review, we will discuss the physiological role of IL-7 with particular emphasis on what is known about the biological basis of its action at dierent lymphoid stages. We will discuss what has been learned about IL-7 receptor engagement, describe subsequent signal transduction pathways, and elaborate on potential in- tracellular mechanisms by which IL-7 may function. In the ®nal sections of this review we will focus on two aspects of the biological requirements for IL-7 in lym- phoid cells. IL-7 has a trophic action on lymphoid progenitors [1,2], maintaining viability of precursor cells independent of cell division. In addition, IL-7 promotes V(D)J recombination in several dierent ways [3±7]. Fig. 1 illustrates the major points we will discuss regarding the response of cells to IL-7. Beyond development, mature lymphoid cells also respond to IL-7 [8] and this has suggested promising therapeutic possibilities for IL-7. However, the reader should be aware that in the quest of understanding how IL-7 functions in physiological processes, we have had to neglect the many promising studies of its therapeutic potential. 2. Role of IL-7 in lymphoid development IL-7 was originally discovered based on its activity in inducing proliferation of murine pro-B cells [9]. It is now recognized that IL-7 plays a critical role in the development of both T and B cells in mice, and of T cells (but not B cells) in man. Early work using recom- binant IL-7 protein revealed that this cytokine is capable of greatly expanding lymphocyte populations, leading to profound increases in both the B and T cell Cytokine & Growth Factor Reviews 10 (1999) 41±60 1359-6101/99/$ - see front matter Published by Elsevier Science Ltd. PII: S1359-6101(98)00025-2 * Corresponding author. Tel.: 301±846±1545, fax: 301±846±6720. E-mail address: durums@mail.ncifcrf.gov (S.K. Durum)