CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells.
ABSTRACT Toll-like receptor (TLR) ligands are notable for their ability to induce APC maturation, which in turn facilitates optimal T cell mediated immune responses. Toll-like receptor ligands, such as CpG DNA, can also modulate immune responses by blocking the suppressive effects of CD4+CD25+ regulatory T cells (Tregs). Recently, we have demonstrated that CpG DNA, in addition to its actions on APCs and Tregs, can provide direct costimulatory signals to CD4+CD25- T cells. Here we show that this costimulatory effect is sufficient to abrogate suppression by Tregs. These data indicate a previously undefined role for TLR ligands in directly modulating CD4+ T cell responses.
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ABSTRACT: Pattern recognition receptors (PRR), like Toll-like receptors (TLR) and NOD-like receptors (NLR), are involved in the detection of microbial infections and tissue damage by cells of the innate immune system. Recently, we and others have demonstrated that TLR2 can additionally function as a costimulatory receptor on CD8 T cells. Here, we establish that the intracytosolic receptor NOD1 is expressed and functional in CD8 T cells. We show that C12-iEDAP, a synthetic ligand for NOD1, has a direct impact on both murine and human CD8 T cells, increasing proliferation and effector functions of cells activated via their T cell receptor (TCR). This effect is dependent on the adaptor molecule RIP2 and is associated with an increased activation of the NF-κB, JNK and p38 signaling pathways. Furthermore, we demonstrate that NOD1 stimulation can cooperate with TLR2 engagement on CD8 T cells to enhance TCR-mediated activation. Altogether our results indicate that NOD1 might function as an alternative costimulatory receptor in CD8 T cells. Our study provides new insights into the function of NLR in T cells and extends to NOD1 the recent concept that PRR stimulation can directly control T cell functions.PLoS ONE 01/2012; 7(7):e42170. · 4.09 Impact Factor
Article: IL-7 Abrogates Suppressive Activity of Human CD4+CD25+FOXP3+ Regulatory T Cells and Allows Expansion of Alloreactive and Autoreactive T Cells.[show abstract] [hide abstract]
ABSTRACT: CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) control the activation and expansion of alloreactive and autoreactive T cell clones. Because uncontrolled activation and expansion of autoreactive T cells occur in an IL-7-rich environment, we explored the possibility that IL-7 may affect the function of Treg. We show that the functional high-affinity IL-7R is expressed on both naive and memory Tregs, and exposure to IL-7 results in STAT-5 phosphorylation. Naive, but not memory, Tregs proliferated greatly and acquired a memory phenotype in the setting of a suppression assay when IL-7 was present. Importantly, the presence of IL-7 abrogated the capacity of Tregs to suppress proliferation of conventional T cells in response to TCR activators, including alloantigens and autoantigens. Removal of IL-7 restored the suppressive function of Tregs. Preblocking of the IL-7R on the Tregs also restored suppressor function, indicating that IL-7 directly affected Treg function. Thus, prolonged periods of homeostatic expansion can temporarily release natural regulatory brakes on T cells, thereby providing an additional mechanism for activating and expanding alloreactive and autoreactive T cells.The Journal of Immunology 11/2012; · 5.79 Impact Factor