Tumor necrosis factor‐α production induced in T lymphocytes through the AIM/CD69 activation pathway

Liu

et al. 2006

The ability of dendritic cells (DC) to initiate immune responses or induce immune tolerance is strictly dependent on their maturation state. TNF-α plays a pivotal role in the differentiation and maturation of DC. Blockade of TNF-α action may arrest DC in an immature state, prolonging their window of tolerogenic opportunity. Immature DC (imDC) were transfected with recombinant adenovirus to express soluble TNF-α receptor type I (sTNFRI), a specific inhibitor of TNF-α. The capacity of sTNFRI gene-modified imDC (DC-sTNFRI) to induce immune tolerance was analyzed. sTNFRI expression renders imDC resistant to maturation induction and impairs their capacity to migrate or present Ag. This process leads to induction of allogeneic T cell hyporesponsiveness and the generation of IL-10-producing T regulatory-like cells. In vivo pretreatment of transplant recipients with DC-sTNFRI induces long-term survival of cardiac allografts in 50% of cases, and leads to a substantial increase in the generation of microchimerism and T regulatory cell numbers. Thus, blockade of TNF-α action by sTNFRI genetic modification can inhibit the maturation of DC and potentiate the in vivo capacity of imDC to induce donor-specific immune tolerance and prolong allograft survival.

Section: Discussionmentioning

confidence: 95%

Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor

Liu

et al. 2006

“…CD69 is a hemopoietic C-type lectin receptor, whose gene is located in the NK gene complex, clustered with the genes for other membrane receptors that regulate NK cell functions, such as CD94/NKG2 heterodimers, NKG2-D, and NKR-P1 (18 -21). CD69 is rapidly induced on NK and other hemopoietic cells in response to cytokines or other activating stimuli (24,25) and has been shown to induce cytotoxic activity and costimulate cytokine production of activated NK cells and T cell clones (4,5,26,27). It thus represents one of the receptors that endow activated NK cells with new recognition capability in the context of natural killing activity (3)(4)(5)(6)(7).…”

Section: Discussionmentioning

confidence: 99%

“…CD69 cross-linking induces the cytotoxic activity and costimulates cytokine production of activated NK cells and selected T cell clones, thus representing a putative receptor for target cells of activated cytotoxic lymphocytes (4,5,24,26,27).…”

mentioning

confidence: 99%

Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells

Pisegna

Zingoni

Pirozzi

et al. 2002

CD69 C-type lectin receptor represents a functional triggering molecule on activated NK cells, capable of directing their natural killing function. The receptor-proximal signaling pathways activated by CD69 cross-linking and involved in CD69-mediated cytotoxic activity are still poorly understood. Here we show that CD69 engagement leads to the rapid and selective activation of the tyrosine kinase Syk, but not of the closely related member of the same family, ZAP70, in IL-2-activated human NK cells. Our results indicate the requirement for Src family kinases in the CD69-triggered activation of Syk and suggest a role for Lck in this event. We also demonstrate that Syk and Src family tyrosine kinases control the CD69-triggered tyrosine phosphorylation and activation of phospholipase Cγ2 and the Rho family-specific exchange factor Vav1 and are responsible for CD69-triggered cytotoxicity of activated NK cells. The same CD69-activated signaling pathways are also observed in an RBL transfectant clone, constitutively expressing the receptor. These data demonstrate for the first time that the CD69 receptor functionally couples to the activation of Src family tyrosine kinases, which, by inducing Syk activation, initiate downstream signaling pathways and regulate CD69-triggered functions on human NK cells.

“…As a membrane receptor, CD69 is rapidly and transiently expressed on the activated lymphocytes, but not on the resting lymphocytes (16,17). Engagement of CD4 T cells with agonistic anti-CD69 mAbs can induce CD4 ϩ T cells to secrete IL-2 and TNF-␣ in the presence of phorbol esters, suggesting that CD69 may exert an activating function to trigger proinflammatory responses (18,19). However, Sancho and colleagues proved that CD69-deficient mice develop an exacerbated form of collageninduced arthritis with higher T and B cell responses against collagen, in which hyperresponsiveness correlates with reduced levels of TGF-␤ in inflamed joints, suggesting that CD69 may also exert a regulatory function (20).…”

Section: Cd25mentioning

confidence: 99%

CD69+CD4+CD25− T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-β1

Yun

Guo

Zhang

et al. 2009

165

The underlying mechanisms of tumor-induced immune suppression need to be fully understood. Regulatory T (Treg) cells have been shown to play an important role in tumor immune escape. Until now, many subsets of Treg cells have been described that can suppress T cell response via different mechanisms. CD69 is generally regarded as one of the activating markers; however, recent studies show that CD69 may exert regulatory function in the immune response. In this study, we have identified tumor-induced CD69+CD4+CD25− T cells as a new subset of CD4+ Treg cells. CD69+CD4+CD25− T cells increase dramatically along tumor progression, with up to 40% of CD4+ T cells in the advanced tumor-bearing mice. Distinct from the previously described CD4+ Treg cell subsets, CD69+CD4+CD25− T cells express high CD122, but they do not express Foxp3 and secrete IL-10, TGF-β1, IL-2, and IFN-γ. CD69+CD4+CD25− T cells are hyporesponsive and can suppress CD4+ T cell proliferation in a cell-cell contact manner. Interestingly, the fixed CD69+CD4+CD25− T cells still have suppressive activity, and neutralizing Abs against TGF-β1 can block their suppressive activity. We found that CD69+CD4+CD25− T cells express membrane-bound TGF-β1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-β1 on CD69+CD4+CD25− T cells via ERK activation. Our results demonstrate that CD69+CD4+CD25− T cells act as a new subset of regulatory CD4+ T cells, with distinct characteristics of negative expression of Foxp3, no secretion of IL-10, but high expression of CD122 and membrane-bound TGF-β1. Our data contribute to the better understanding of mechanisms for tumor immune escape.