Either IL-2 or IL-12 Is Sufficient to Direct Th1 Differentiation by Nonobese Diabetic T Cells

Abstract

Th cell differentiation from naive precursors is a tightly controlled process; the most critical differentiation factor is the action of the driving cytokine: IL-12 for Th1 development, IL-4 for Th2 development. We found that CD4+ T cells from nonobese diabetic mice spontaneously differentiate into IFN-γ-producing Th1 cells in response to polyclonal TCR stimulation in the absence of IL-12 and IFN-γ. Instead, IL-2 was necessary and sufficient to direct T cell differentiation to the Th1 lineage by nonobese diabetic CD4+ T cells. Its ability to direct Th1 differentiation of both naive and memory CD4+ T cells was clearly uncoupled from its ability to stimulate cell division. Autocrine IL-2-driven Th1 differentiation of nonobese diabetic T cells may represent a genetic liability that favors development of IFN-γ-producing autoreactive T cells.

Impaired IL‐4 production by CD8+ T cells in NOD mice is related to a defect of c‐Maf binding to the IL‐4 promoter

“…2A). Although NOD CD4 + T cells appeared to produce lower levels of IL-4 in neutral conditions, consistent with a recent report [12], culture in type 2 conditions induced a significant increase in IL-4 production in all three strains, which was highly significant (p=0.0039) in the case of NOD.…”

“…A majority of studies have pointed to a correlation between the development of diabetes in NOD mice and an enhanced type 1 immune response by NOD CD4 + T cells [11,12] or dendritic cells [13,14] and a decreased type 2 immune response by CD4 + T cells [15]. Furthermore, T cells from individuals with type 1 diabetes produced higher levels of IFN-c compared to healthy controls [16].…”

Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation

“…Histone hyperacetylation is also involved in the function of genomic nuclear matrix attachment regions and other nuclear functions that regulate gene transcription (8,28). For example, genomic regions that are involved in the regulation of transcription of linked genes under common control but are positioned kilobases away from the genes they regulate also exhibit histone hypo-and hyperacetylation patterns over extended chromatin domains (19)(20)(21). Histone H3 and H4 hyperacetylation of the Ifng promoter has been previously reported in T cells stimulated under Th1 differentiation conditions (6,7).…”

“…Studies in tissue culture models, by us and others, demonstrate that, in contrast to other murine strains, CD4 ϩ T cells from the autoimmune prone nonobese diabetic (NOD) strain are genetically programmed to use IL-2 as a driving cytokine to differentiate into IFN-␥-producing effector T cells (21)(22)(23). Thus, an antigen stimulus is sufficient to drive both T cell proliferation and Th1 differentiation.…”

Lactobacillus gasseri OLL2809 inhibits development of ectopic endometrial cell in peritoneal cavity via activation of NK cells in a murine endometriosis model

“…Somigliana et al have shown that peritoneal administration with interleukin-12p70 (IL-12) to experimental endometriosis mice resulted in suppression of development of endometriotic lesions (Somigliana et al 1999). IL-12 is well known to induce Th1 proliferation followed by activation of NK cells by secreting Th1-cell derived cytokines such as IL-2 and interferon-gamma (IFN-c) (Chan et al 1992;Zhou et al 2003). We recently observed suppressive effect of IL-12 on development of ectopic endometriotic lesions and found it was due to activation of natural killer (NK) cells because anti-IL-2 receptor b chain treatment resulted in attenuation of splenic cytotoxicity of NK cells concomitant with suppression of development of endometriotic lesions (Itoh et al 2011).…”