IL-15 induces type 1 and type 2 CD4+ and CD8+ T cells proliferation but is unable to drive cytokine production in the absence of TCR activation or IL-12 / IL-4 stimulationin vitro

Abstract

Interleukin 15 (IL‐15) is a pleiotropic cytokine produced principally by monocytes and affects both innate and acquired immunity. It has been shown that IL‐15 is essential for the proliferation and maintenance of CD8+ memory cells but has little or no effect on naive CD8+ cells or CD4+ T cells. We report here, using an in vitro culture system of antigen‐specific OVA TCR transgenic T cells as well as normal mouse T cell activated with anti‐CD3 antibody that IL‐15, at high concentrations, induced proliferation of both naive and memory CD4+and CD8+ cells. IL‐15 also enhanced the differentiation of type 1 (IFN‐γ‐producing) and type 2 (IL‐5‐producing) CD4+ and CD8+ T cells under IL‐12 and IL‐4 driving conditions, respectively. However, IL‐15 alone was not efficient in stimulating cytokine production of these cells in the absence of T cell subset driving cytokines (IL‐12 or IL‐4) and / or simultaneous TCR activation. Together, these results demonstrate that IL‐15, at high dose, is a pan‐T cell growth factor. The apparent requirement of IL‐15 for the maintenance of memory CD8+ cell in vivo may reflect the exceptionally restricted nature of this subpopulation of cells for IL‐15. The inability of IL‐15 alone to stimulate cytokine synthesis also suggests that IL‐15 on its own doesnot drive antigen‐specific T cells to exhaustion. The levels of these cells are maintained by IL‐15 and they are only mobilized to carry out effector functions when subsequently confronted with specific pathogens.

Profound Enhancement of the IL-12/IL-18 Pathway of IFN-γ Secretion in Human CD8+ Memory T Cell Subsets via IL-15

“…Because of the possibility of a small number of contaminating cells in CD8 ϩ columnpurified populations (which were 90 -95% pure), we only measured IFN-␥ in culture supernatants from FACS-sorted cells. A study (28) in mice reported that IL-15 in itself could not directly induce IFN-␥ secretion, which is in agreement with our observations. We hypothesize that IL-15 is necessary, but not sufficient to induce CD8 ϩ T cell effector functions.…”

Effect of interleukin-15 on effector and regulatory function of anti-CD3/anti-CD28-stimulated CD4+ T cells

“…Loss of CD62L expression on CD4 þ T cells has been associated with effector memory transformation 18 and activation-induced apoptosis. 19 In agreement with Niedbala et al, 20 cytokine production studies revealed that IL-15 enhanced both Th1 (IFN-g and TNF-a) and Th2 cytokines (IL-5 and IL-10) of CD3/CD28-activated CD4 þ T cells, but not IL-2 and IL-4 production. Previous studies demonstrated that CD62-negative and -positive subpopulations of human CD45RO þ CD4 þ T cells represent characteristics of Th1 and Th2, respectively.…”

Interleukin‐15 stimulates macrophages to activate CD4+ T cells: a role in the pathogenesis of rheumatoid arthritis?

“…4 The assumed specificity of IL-15 for CD8 + T cells (as seen in many models and in the initial reports about IL-15 and IL-15Ra knockout mice 27,28 ) has recently been demonstrated to be a dosedependent effect, because high IL-15 doses also potently activate CD4 + T cells. 29 However, besides a direct effect of IL-15 on CD4 + T cells, we propose a new aspect of this cytokine by activating monocytes to induce and/or support CD4 + T-cell proliferation. Since IL-15 trans-presentation has already been demonstrated to be effective for CD8 + T cells, NK cells and germinal B cells, but to our knowledge not for CD4 + T cells, it deserves careful future exploration, especially in the context of RA.…”