Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.

IntroductionT helper (Th) cells may differentiate into distinct functional subsets according to the circumstances in which naive precursors encounter the nominal antigen for which they are specific. In the presence of interleukin-12 (IL-12), Th precursor cells become Th1 and high producers of interferon-␥ (IFN-␥), whereas in the presence of IL-4 they become Th2 and high producers of IL-4 and IL-5. These subsets have fundamentally different effector functions, in particular for their capacity to induce monocytes activation. 1 Recently, a distinct Th subset has been characterized in mice 2-6 and humans [7][8][9][10][11] for its high production of IL-17, the use of retinoid-related orphan receptor ␥t (ROR␥t) as master transcription factor, 12 its role in protection against extracellular bacteria and fungi, and in the pathogenesis of several autoimmune conditions, such as collageninduced arthritis, experimental autoimmune encephalomyelitis, and an animal model of inflammatory bowel disease. 4,13,14 Of interest, the generation of Th17 from naive precursors may follow different requirements in mice and humans. In mice, commitment to the Th17 lineage is dependent on transforming growth factor-␤ (TGF-␤), IL-1␤, and IL-6, whereas in humans IL-1␤ and IL-6 but not TGF-␤ appear to be required. 10,[15][16][17][18] The role of IL-23 in Th17 differentiation and effector function is still debated. IL-23 is a member of the IL-6 family of cytokines that shares with IL-12 the p40 subunit and has a unique p19 subunit. 19 IL-23 promotes Th17 responses in vivo but may be more important for the survival and population expansion of Th17 cells than for Th17 lineage commitment. 3,5,16 However, in conjunction with IL-1, IL-23 is sufficient for inducing naive human T cells to produce IL-17A, IL-17F, IL-22, IL-26, IFN-␥, C-C chemokine ligand 20 (CCL20)/ macrophage inflammatory protein 3␣ (MIP-3␣), and the transcription factor ROR␥t. 10 Moreover, mice lacking IL-23 are fully resistant to experimental autoimmune encephalomyelitis, collageninduced arthritis, and inflammatory bowel disease.The pattern of chemokine receptors expressed varies according to the differentiation stage and effector function of T cells. 20 The preferential expression of C-C chemokine receptor 6 (CCR6) distinguishes human Th17 from other Th subsets. 7,8,21,22 It should be stressed, however, that expression of CXC chemokine receptor 3 (CXCR3) within CCR6 ϩ T cells identifies T cells with preferential IFN-␥ production in response to purified protein derivative, whereas IL-17 production in response to Candida albicans hyphae is restricted to CCR6 ϩ CCR4 ϩ cells. 7 IL-17, when overexpressed in murine knee joint, causes inflammation and bone erosion. 23 Likewise, erosion observed in streptococcal cell wall-induced arthritis is highly reduced in IL-17R Ϫ/Ϫ and is associated with impaired expression of matrix metalloproteinases (MMPs). 24 T-cell clones producing IL-17 were generated from the synovium and synovial fluid of rheumatoid arthritis patients, 25 and IL-17 was shown t...

Natural killer (NK) cells play a crucial role in the immune response to micro-organisms and tumours. Recent evidence suggests that NK cells also regulate the adaptive T-cell response and that it might be possible to exploit this ability to eliminate autoreactive T cells in autoimmune disease and alloreactive T cells in transplantation. Mature NK cells consist of a highly diverse population of cells that expresses different receptors to facilitate recognition of diseased cells and possibly pathogens themselves. Ex vivo culture of NK cells with cytokines such as IL-2 and IL-15 is an approach that permits significant expansion of the NK cell subpopulations, which are likely to have potent antitumour, antiviral, or immunomodulatory effects in autoimmunity. Our data indicate that the addition of IL-21 has a synergistic effect by increasing the numbers of NK cells on a large scale. IL-2 and IL-15 may induce the expression of killer cell immunoglobulin-like receptors (KIRs) in KIRnegative populations, the c-lectin receptor NKG2D and the natural cytotoxic receptor NKp44. The addition of IL-21 to IL-15 or IL-2 can modify the pattern of the KIR receptors and inhibit NKp44 expression by reducing the expression of the adaptor DAP-12. IL-21 also preserved the production of interferon-γ and enhanced the cytotoxic properties of NK cells. Our findings indicate that the proinflammatory cytokines IL-2, IL-15 and IL-21 can modify the peripheral repertoire of NK cells. These properties may be used to endow subpopulations of NK cells with specific phenotypes, which may be used in ex vivo cellular immunotherapy strategies.

In solid organ transplanted patients, annual influenza immunization is strongly recommended because of morbidity and mortality of influenza infections. In 2009, the rapid spread of a novel H1N1 influenza A virus led to the accelerated development of novel pandemic influenza vaccines. In Switzerland, the recipients received one dose of seasonal influenza and two doses of AS03-adjuvanted H1N1 vaccines. This situation provided a unique opportunity to analyze the influence of novel adjuvanted influenza vaccines on the production of de novo anti-HLA antibodies. We prospectively followed two independent cohorts including 92 and 59 kidney-transplanted patients, assessing their anti-HLA antibodies before, 6 weeks and 6 months after vaccination. Sixteen of 92 (17.3%) and 7 of 59 (11.9%) patients developed anti-HLA antibodies. These antibodies, detected using the single antigen beads technology, were mostly at low levels and included both donor-specific and non-donor-specific antibodies. In 2 of the 20 patients who were followed at 6 months, clinical events possibly related to de novo anti-HLA antibodies were observed. In conclusion, multiple doses of influenza vaccine may lead to the production of anti-HLA antibodies in a significant proportion of kidney transplant recipients. The long-term clinical significance of these results remains to be addressed.Key words: Antibody-mediated rejection, H1N1 immunization, HLA antibodies, kidney transplantation, Luminex assay Abbreviations: DSA, donor-specific antibody; HLA, human leukocyte antigen; MFI, mean fluorescence intensity.