Endogenously Produced IL-4 Nonredundantly Stimulates CD8+ T Cell Proliferation

Abstract

T cell proliferation and survival are regulated by the cytokine receptor common γ-chain-associated cytokines IL-2, IL-7, and IL-15, while IL-4, another γ-chain-associated cytokine, is thought to primarily affect T cell quality rather than quantity. In contrast, our experiments reveal that endogenously produced IL-4 is a direct, nonredundant, and potent stimulator of CD8+ T cell proliferation in Ag- and pathogen-induced CD8+ T cell responses. These stimulatory effects of IL-4 are observed in both BALB/c and C57BL/6 mice and activate both naive and memory/activated phenotype CD8+ T cells, although the former are stimulated less than are the latter. IL-4 effects are IL-7- and IL-15-independent, but MHC class I-dependent stimulation appears to be required for the mitogenic effect of IL-4 on naive phenotype CD8+ T cells. Thus, endogenously produced IL-4 is an important regulator of quantitative as well as qualitative aspects of T cell immunity.

IFN-γ Inhibits IL-4–Induced Type 2 Cytokine Expression by CD8 T Cells In Vivo and Modulates the Anti-Tumor Response

“…Somewhat paradoxically, we found that IFN-g +/+ or IFN-g 2/2 OT-I cells activated in the presence of IL-4 and then transferred to new hosts were significantly reduced in number in the spleen following tumor challenge with the parental EG7 tumor line. One possible interpretation of this finding is that the IL-4-exposed donor cells did not survive as well as the non-IL-4-exposed cells; this notion is supported by recent evidence that CD8 T cells activated in the presence of IL-4 become IL-4 dependent for survival (2). An alternate interpretation may be that the IL-4-exposed CD8 T cells have different homing abilities and survive in organs other than the spleen or lymph nodes or within the tumors.…”

“…For example, IL-4 can enhance CD8 T cell expansion during an immune response (2), modulate the functional avidity of the TCR by reducing CD8 coreceptor expression (3-7), promote CD8 T cell survival by upregulating the expression of the anti-apoptotic molecule Bcl-x L (8), and induce the development of effector CD8 T cells that can express type 2 as well as type 1 cytokines (6, 9, 10). Early work in mice showed that IL-4 exposure induced the loss of CD8 expression and cytolytic function of CD8 T cells in vitro (6).…”

In vivo IL-4 prevents allo-antigen driven CD8+ CTL development

“…Because host CD8 + T cells can limit GVHD by either differentiating into Tc2 cells (22) or by participating in a HVG reaction (17, 20) and IL-4 can stimulate CD8 + T cell proliferation in the absence of GVHD (23), we evaluated whether IL-4C has a stimulatory effect on host CD8 + T cells in the context of acute GVHD. Using the mice described in Fig.…”

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

“…This has been shown to induce memory CD8 T cell proliferation in vivo (16) and to mimic the impact of IL-4 on CD8 T cells that is observed during a Th2 response induced by parasites or allergens (19). These complexes are used because rIL-4 has a very short t 1/2 in vivo, and it has been shown that its association with the anti-IL-4 mAb 11b11 increases both biodisponibility and t 1/2 of IL-4 in the mouse (34).…”

“…IL-4 acted directly on CD8 T cells as neither Stat6-nor Il4ra-deficient CD8 T cells did proliferate when NKT cells were stimulated to produce IL-4 (17). Th2 CD4 T cells induced by parasitic infection or allergen produce IL-4 that induces STAT6 phosphorylation and homeostatic proliferation of memory-phenotype CD8 T cells (18,19). Recently, it has also been shown that the IL-4 produced by NKT cells drives the differentiation of CD8 single-positive thymocytes into memory-like CD8 T cells that have recently been renamed innate CD8 T cells (20,21).…”