IL-15Rα expression on CD8⁺T cells is dispensable for T cell memory

Abstract

The generation and maintenance of immunological memory requires the activation, expansion, and persistent proliferation of antigen-specific T cells. Recent work suggests that IL-15 may be important for this process. Surprisingly, we now find that expression of the high-affinity receptor for IL-15, IL-15R␣, on T cells is dispensable for the generation or maintenance of memory CD8 ؉ T cells. By contrast, IL-15R␣ expression on cells other than T cells is absolutely critical for this function. These findings may be related to IL-15R␣'s ability to present IL-15 in trans to low-affinity IL15R␤͞␥c receptors on memory CD8 ؉ T cells. These unexpected results provide insights into how IL-15R␣ supports memory CD8 ؉ T cells.M emory CD8 ϩ T cells are critical mediators of immunity to intracellular pathogens. The signals that support homeostasis of memory CD8 ϩ T cells have only recently begun to be elucidated. Unlike their naïve counterparts, memory CD8 ϩ T cells do not require interaction with cognate MHC (1). Rather, cytokines that use the common ␥ (␥ c ) chain for receptor signaling appear to play a central role in the support of memory CD8 ϩ T cells. Two such cytokines, IL-7 and IL-15, have been shown to regulate memory CD8 ϩ T cell homeostasis. However, whereas IL-7 primarily supports proliferation of both naïve and memory CD8 ϩ T cells in lymphopenic states, IL-15 specifically regulates the survival and proliferation of memory CD8 ϩ T cells under normal physiological conditions. IL-15 is a four-␣-helix bundle family cytokine both functionally and structurally similar to IL-2 (2, 3). The heterotrimeric IL-15 receptor (IL-15R) consists of IL-15R␣, which uniquely binds IL-15, as well as IL-2R␤ and ␥ c (4, 5). IL-15R␣ alone binds IL-15 with a K d of Ϸ1 ϫ 10 Ϫ11 M. Consistent with IL-15's functional homology to IL-2, IL-15R shares IL-2R␤ and ␥ c subunits with IL-2R, and these subunits mediate signaltransduction events after IL-2 or IL-15 binding. Whereas IL-2R␤ and ␥ c are able to bind IL-15 without IL-15R␣, the similar phenotypes of IL-15 Ϫ/Ϫ and IL-15R␣ Ϫ/Ϫ mice suggest that IL-15R␣ is required for IL-15 signals in vivo.Several lines of evidence suggest that IL-15 selectively supports the survival and proliferation of both memory and memory phenotype (CD44 Hi IL-2R␤ Hi ) CD8 ϩ T cells. First, memory phenotype cells express high levels of IL-2R␤, a key component of the IL-15R complex, and in vivo administration of anti-IL-2R␤-specific, but not anti-IL-2R␣-specific, antibodies blocks the basal proliferation of these cells (6). Second, administration of recombinant IL-15 selectively stimulates the proliferation of memory phenotype CD8 ϩ T cells both in vivo and in vitro (7). Third, both IL-15 Ϫ/Ϫ and IL-15R␣ Ϫ/Ϫ mice have severely reduced numbers of memory phenotype cells, whereas mice that overexpress a readily secreted form of IL-15 possess increased numbers of these cells (8-10). Finally, recent studies using IL-15 Ϫ/Ϫ or IL-15R␣ Ϫ/Ϫ mice suggest that antigen-experienced CD8 ϩ memory T cells require both IL-15 and IL-15R␣...

Impaired Protection against Mycobacterium bovis Bacillus Calmette-Guérin Infection in IL-15-Deficient Mice

“…IL-15 is important in maturation of dendritic cells (DCs) for Ag presentation (36), suggesting that generation of effector CD8 ϩ T cells may be impaired at the expansion phase after BCG infection, resulting in a decrease in the number of Ag-specific CD8 ϩ T cells in the lung at the late stage of infection. Recent studies have demonstrated that primary responses to LCMV and OVA were readily generated in IL-15 Ϫ/Ϫ mice or IL-15R␣ Ϫ/Ϫ mice to a level equal to that in control mice (24,37). We have also reported that generation of Ag-specific CD8 ϩ T cells in IL-15 Tg mice and IL-15 Ϫ/Ϫ mice normally occurred after primary infection with L. monocytogenes (38,39).…”

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

“…Whereas IL-7 promotes the survival of both naive and memory CD8 + T cells, IL-15 uniquely supports basal memory CD8 + T cell proliferation [20,41,48]. Thus, in the absence of proliferative IL-15 signals, effector/memory CD8 + T cells undergo slow atrophy in number until they become essentially undetectable under certain conditions [20,49]. After infection with Mtb, we now show that the accumulation of CD8 + T cells in the lungs of IL-15 -/-mice was indeed substantially reduced.…”

Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form

“…Recent data suggest that IL-15R␣ not only acts as a component of IL-15R complex for the high affinity binding, but can also act to present IL-15 to adjacent cells in vitro and in vivo (40,41,65,67,72). In the GC reaction, effective delivery of survival and proliferative signals only to appropriate clones having higher affinity BCR is essential so as not to expand overwhelming numbers of clones with low affinity BCR.…”