Cytokine functions in the formative stages of a lymphocyte’s life
Introduction
Cells develop within a three dimensional space in constant communication with their surroundings. It is becoming apparent that properties of the space and the lymphoid progenitors change over time. The complex and dynamic interactions between the developing lymphocytes and the local milieu take two general forms: secreted (diffusible or localized) factors or cell–cell contact-dependent signals. Of the former, cytokines are the best characterized. The principle cytokines controlling development of the major lymphoid lineage cells from the lymphoid-lineage-committed progenitors have been identified: T-cell development requires IL-7 and stem cell factor (SCF); the B-cell lineage is dependent on IL-7, thymic stromal lymphopoietin (TSLP) and fetal liver kinase 2 ligand (Flk-2L); and the primary cytokines regulating natural killer (NK)-cell development are IL-15 and Flk-2L. This review focuses on the newly emerging details of the mechanisms by which these core cytokines, with a special emphasis on IL-7, regulate differentiation, survival and proliferation of lymphocytes in space and time.
Section snippets
The function of IL-7 and the related cytokine thymic stromal lymphopoietin in lymphopoiesis
IL-7 is the critical cytokine for T- and B-cell development in mice. It is required for T- and B-precursor-cell maturation and survival, CD8+ thymocyte positive selection, and regulation of T-cell receptor γ (TCRγ) and IgH locus accessibility to the V(D)J recombinase. IL-7 receptor (IL-7R) signaling is essential for the generation and maintenance of precursor cells committed to either the T or B lineage. IL-7 is a member of the γc chain cytokine receptor superfamily that includes other key
IL-7 function is dependent on quantitative calibration of signal strength
Whereas IL-7Rγc expression is relatively ubiquitous, IL-7Rα chain expression is highly regulated in a developmental-stage-specific manner. Among the progenitor subsets, the α chain is expressed on CLPs of the bone marrow but not on hematopoietic stem cells (HSCs) or myeloid-committed progenitors. It is also clear that the newly defined earliest thymic progenitor (ETP) in the adult thymus is IL-7Rneg/lo and is not responsive to IL-7 in vitro [10•]. Combined with the normal number of CLPs in
IL-7 and cell survival: more than just Bcl-2?
The notion that IL-7 is primarily a survival factor that induces anti-apoptotic Bcl-2 protein expression has been widely disseminated [19]. IL-7 is thought to maintain viability of the precursor population and the thymocytes selected to progress to terminal maturation, especially during the positive thymic selection of the CD8+ T lineage [20]. It is clear that IL-7 signaling modulates Bcl-2 expression in the T-cell lineage [21], although this activity is not unique to IL-7, as other γc
IL-7 controls differentiation by promoting increased chromatin accessibility at the antigen receptor gene loci
With respect to the core cytokines, the life of T and B cells can be divided into two phases: before and after antigen receptor gene rearrangement and expression. In general, the core cytokines exert a more primary influence when antigen receptors are not expressed or not fully engaged, as in the early precursor cell survival and expansion and in peripheral T-cell homeostasis. It is unlikely to be a coincidence that IL-7R downmodulation occurs as developing cells acquire antigen receptors. In
IL-7 in precursor B-cell proliferation
IL-7 was originally characterized as a growth factor for immature and mature lymphocytes. Recent findings, however, indicate that although IL-7 is indeed a potent stimulator of immature B-cell expansion [32], it alone is not sufficient to promote precursor T-cell division. Increased concentration of IL-7 or the overexpression of STAT5 in fetal thymic organ cultures (FTOCs) did not lead to increased thymic cellularity (J Kang et al., unpublished; [37]). Similarly, IL-7 transgenic mice exhibit
Regulation of and requirement for c-Kit and Flk-2 signaling in lymphopoiesis
Although the core cytokines are absolutely required for proper lymphocyte development, it has become clear that additional classes of secreted factors are critical for ensuring normal survival and proliferative traits of immature lymphocytes. Some of these factors might work in parallel with the cytokine signaling pathway with a point of intersection for mutual regulation. The best-characterized example of this class of regulators is the WNT family of molecules [54]. It has been well documented
The signaling specificity of cytokines
In vivo cytokine-specific function naturally evokes the notion that different cytokines signal distinctly. Experimental evidence for this thesis is sparse. Indeed, the commonality of signaling pathways exists not only within a cytokine superfamily, but extends to encompass many distinct classes of cytokines. For example, nearly all type I and II cytokine receptor families can active the JAK–STAT, PI3K and MAPK pathways. Hence, the in vivo specificity of cytokine action can be seen as the
Inhibitory circuits in cytokine signaling
Given the importance of phosphorylation events in positive regulation of cytokine signal transduction, many negative regulatory mechanisms target phosphorylated proteins (Figure 1). The phosphatase SHP1 (SH2-containing tyrosine phosphatase) binds to JAK1 and JAK2 to limit further STAT phosphorylation. It also interacts directly with receptor tyrosine kinases, such as c-Kit, to negatively regulate their activity. Shp-1−/− mice (motheaten) show many defects in lymphopoiesis, including early onset
Concluding remarks
Advances in recent years in the identification and characterization of cytokines critical for lymphopoiesis have raised many challenging questions. First, the fundamental issue of the nature of cytokine signaling pathways and/or cell intrinsic properties that determine cytokine functional specificity remain unclear. This issue is greatly confounded by the fact that cytokine requirements for a given cell lineage, and signaling properties of a given cytokine necessary for that lineage, change
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
We would like to thank Heather Melichar and Kavitha Narayan for critical reading of the manuscript. JK is supported by National Institutes of Health grant (AI92614). SD is supported by grants from Canadian Institutes of Health Research and Genome Canada.
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