IL-15 as a mediator of CD4 ⁺ help for CD8 ⁺ T cell longevity and avoidance of TRAIL-mediated apoptosis

Abstract

Antigen-specific CD8 ϩ T cells can be programmed in the immune induction phase (3-5). CD4 ϩ help is needed for induction of long-lived memory CD8ϩ T cells (6, 7). The results of early programming are more profound in secondary responses: CD8 ϩ T cells primed in the absence of CD4 ϩ helper T cells undergo tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and show poor long term memory (8, 9). Thus, understanding the mechanisms by which help from CD4 ϩ T cells prevents CD8 ϩ T cell death and enhances the maintenance of memory CD8 ϩ T cells is critical for developing new vaccines.In addition to the maintenance of CD8 ϩ memory T cells (10-15), we previously found that additional IL-15 provided by a vaccine vector only during priming induced long-lived memory CD8 ϩ T cells (5) and contributed to the long-term avidity maturation of CD8 ϩ T cells (16). These findings suggest that IL-15 contributes to programming of CD8 ϩ T cells to be long-lived cells that can further expand on reexposure to antigen. Therefore, we hypothesized that CD8 ϩ T cells programmed with IL-15 only during priming, even in the absence of CD4 ϩ helper T cells, may overcome TRAIL-mediated apoptosis during secondary responses and persist longer. We also hypothesized that one mechanism by which CD4 ϩ helper T cells help CD8 ϩ T cells is to stimulate IL-15 production by the antigen presenting cells (APCs), including dendritic cells (DCs).Here, we show that IL-15 provided by the vaccine can replace CD4 ϩ helper T cells in inducing long-lasting antigen-specific CD8 ϩ T cells that can efficiently respond to secondary responses.Conversely, help was less effective when DCs did not produce IL-15. Thus, we conclude that IL-15 codelivered with vaccines can overcome CD4 ϩ helper T cell deficiency and that IL-15 may be one mediator of help. These new findings will be important for developing new vaccines against cancers and viral infections, especially those such as HIV that result in diminished CD4 ϩ T cell help. Results IL-15 Substitutes for CD4 ؉ Help in CD8 ؉ T Cell Priming for Long-LivedMemory. To test whether IL-15 can substitute for CD4 ϩ T cells in the induction of longer-lived antigen-specific CD8 ϩ T cells, animals, either CD4-depleted or undepleted, were immunized with recombinant vaccinia viruses expressing HIVgp160 (vPE16) or .CD4 ϩ T cell-undepleted animals immunized with vPE16 maintained P18-I10-specific CD8 ϩ T cells (measured directly ex vivo without restimulation) for 1 year (Fig. 1A). Animals immunized with vPE16-IL-15 had a higher percentage of long-lasting memory CD8 ϩ T cells than those without IL-15 (percentage of peak response remaining, 23% vs. 16%), indicating that IL-15 provided by the vaccine vector contributes to the enhanced induction of long-lasting memory CD8 ϩ CTL in WT animals and that endogenous IL-15 may be limiting. In contrast, in CD4-depleted animals, the majority of the CD8 ϩ T cells induced by vPE16 disappeared shortly after the primary response, with Ͻ1% of the peak response remaining at...

Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques

“…11 Trans presentation of IL-15 by antigenpresenting cells, including dendritic cells, to CD8 T cells contributes to the generation and maintenance of long-lasting, highavidity, antigen-specific CD8 ϩ memory T cells. [12][13][14][15][16][17][18][19][20][21][22][23][24] These observations from ex vivo functional studies are supported by analysis of mice with disrupted cytokine or cytokine-receptor genes. IL-2 and IL-2R␣-deficient mice develop marked enlargements of peripheral lymphoid organs that are associated with polyclonal expansions of T-and B-cell populations and the development of autoimmune disorders.…”

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

“…It is possible that some of the autoreactive TCRs in the polyclonal repertoire may have overcome the dependency on IL-15Ra due to higher affinity of their TCR toward their cognate autoantigens and/or help from donor CD4 1 T cells present in the polyclonal repertoire. 27 Nevertheless, the above results indicate that (i) IL-15 trans-presentation is dispensable for the initial pathogenic activation of diabetogenic T cells, (ii) its requirement for sustaining the pathogenic potential of antigen-experienced CD8 1 T cells may vary depending on the clonal diversity of the autoreactive T cells, and (iii) when required for the latter, IL-15Ra expressed on antigen-experienced CD8 1 T cells likely promotes their homeostatic expansion and/or pathogenic functions.…”

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

“…Studies in mice showed that TLR2, -3, and -9 agonists activate and mature dendritic cells (DCs) to enhance immune responses (8,9) and our laboratory discovered a synergistic adjuvant effect of a combination of these agonists (9,10). We and others have also found that IL-15 is a strong cytokine adjuvant, as it promotes the homeostatic expansion of CD8 + memory T cells, and the induction of higher avidity, longer-lived T cells (11)(12)(13)(14). Combinations of these adjuvants might therefore improve the magnitude and quality of vaccine-induced responses.…”