Preface Common cytokine-receptor γ-chain (γc) family cytokines have critical roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune system. In this review, we focus on our current understanding of the distinct and overlapping effects of IL-2, IL-7, IL-9, IL-15, and IL-21, as well as the IL-7-related cytokine TSLP (thymic stromal lymphopoietin), on the survival and proliferation of conventional αβ T cells, γδ T cells, and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development.

Summary Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a-Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined dimer versus tetramer consensus motifs. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable; thus, STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function, establishing a critical role for tetramerization in vivo.

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Inflammation is a double-edged sword that can promote or suppress cancer progression. Here we report that thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs, is also expressed in human and murine cancers. Our studies with murine cancer cells indicate that TSLP plays an essential role in cancer escape, as its inactivation in cancer cells alone was sufficient to almost completely abrogate cancer progression and lung metastasis. The cancer-promoting activity of TSLP primarily required signaling through the TSLP receptor on CD4+ T cells, promoting Th2-skewed immune responses and production of immunosuppressive factors such as IL-10 and IL-13. Expression of TSLP therefore may be a useful prognostic marker and its targeting could have therapeutic potential.

Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays essential roles in allergic/inflammatory skin and airway disorders, in helminth infections, and in regulating intestinal immunity. TSLP signals via IL-7Rα and a specific TSLPR subunit that is highly related to the common cytokine receptor γ chain, γ c . Although TSLP has effects on a broad range of hematopoetic cells and can induce STAT5 phosphorylation, TSLP was reported to not signal via JAK kinases, and the mechanism by which TSLP regulates STAT5 phosphorylation has been unclear. We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4 + T cells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7. We also show that just as JAK1 interacts with IL-7Rα, JAK2 is associated with TSLPR protein. Moreover, we demonstrate the importance of STAT5 activation for TSLPmediated survival and proliferation of CD4 + T cells. These findings clarify the basis for TSLP-mediated signaling and provide an example wherein a cytokine uses JAK1 and JAK2 to mediate the activation of STAT5.T hymic stromal lymphopoietin (TSLP) is a cytokine produced by stromal cells, epithelial cells, fibroblasts, keratinocytes, and basophils (1-3). Increased TSLP levels are associated with airway inflammatory disease and atopic dermatitis in humans and mice (1,(3)(4)(5). In addition, TSLP regulates intestinal immunity and inflammation (6) and is important in helminth infections (6-8). TSLP is closely related to IL-7, another stromal factor. IL-7 signals via IL-7Rα and the common cytokine receptor γ chain, γ c (9, 10), a protein that is also a critical component of the receptors for and is mutated in humans with X-linked severe combined immunodeficiency (12). In contrast, TSLP signals via IL-7Rα and a specific subunit, TSLPR, that is highly related to γ c (13,14). IL-7 is known to critically control the development, expansion, and survival of naive and memory T cells, thereby regulating the number of mature T cells and maintaining lymphoid homeostasis (11). TSLP can directly act on both mouse and human CD4 + and CD8 + T cells (15-18) and contributes to Tcell lymphopoiesis and homeostasis (15,18,19). However, whereas IL-7 induces proliferation and survival of mouse naive T cells, TSLP preferentially promotes survival, with less of an effect on the proliferation of these cells (15,18). Consistent with this, bone marrow-derived IxN/2B cells, which express TSLPR and IL-7Rα and respond to both TSLP and IL-7 to induce STAT5 phosphorylation, potently proliferate in response to IL-7 but not TSLP (20).Although both IL-7 and TSLP are essential in the mouse for normal B-cell lymphopoesis in vivo (15, 19), IL-7 plays a greater role, as evidenced by the profound B-cell lymphopenia in the absence of IL-7 (21). IL-7 preferentially promotes the generation of B220 + /IgM − pre-B cells from fetal liver lymphocyte precursors, whereas TSLP mediates production of B220 + /IgM + immature B cells (22,23). Interestingly, n...

TSLP is a type 1 cytokine that contributes to lymphopoiesis and the development of asthma and atopic dermatitis. TSLP acts on multiple lineages, including dendritic cells (DCs), T cells, NKT cells, eosinophils, and mast cells, mediating proliferation and survival, and linking innate and adaptive immune responses. TSLP is produced by a range of cells, including epithelial cells, fibroblasts, stromal cells, and keratinocytes. DCs are important primary targets of TSLP, and we now unexpectedly demonstrate that DCs also produce TSLP in response to Toll-like receptor (TLR) stimulation and that this is augmented by IL-4. Moreover, we demonstrate that when mice are challenged with house dust-mite (HDM) extract, lung CD11c+ DCs express TSLP mRNA at an even higher level than epithelial cells. These data suggest that DCs not only respond to TSLP but also are a source of TSLP during pathogen and/or allergen encounter.

Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. Genomic analysis revealed concentration-dependent actions of IRF4 and IRF8 in regulating distinct gene-expression programs. Stochastic modeling suggested that the double-negative feedback was sufficient to initiate bifurcation of the B cell developmental trajectories.

Thymic stromal lymphopoietin (TSLP) is a cytokine produced by stromal cells, epithelial cells, and basophils that acts on dendritic cells, mast cells, and CD4+ T cells. The receptor for TSLP contains a TSLP-specific receptor chain (TSLPR) and the IL-7R α-chain. Although IL-7 critically controls the expansion and survival of naive and memory CD8+ T cells, an action for TSLP on CD8+ T cells has not been reported. We now demonstrate that CD8+ T cells express TSLPR and that TSLP activates both STAT5 and Akt and induces Bcl-2 in these cells. Correspondingly, TSLP increases CD8+ T cell survival in vitro as well as in wild-type and T-depleted mice in vivo, without altering the homeostatic proliferation of these cells. Moreover, TSLP can maintain CD8+ T cells even in the absence of IL-7. Thus, our data reveal that TSLP contributes to CD8+ T cell homeostasis in both normal and lymphopenic conditions.