Critical Role of TNF Receptor Type-2 (p75) as a Costimulator for IL-2 Induction and T Cell Survival: A Functional Link to CD28

Abstract

CD28 provides important signals that lower the threshold of T cell activation, augment the production of IL-2, and promote T cell survival. The recent identification of a second family of costimulatory molecules within the TNFR family has reshaped the “two-signal” model of T cell activation. In this study the role of p75 as a T cell costimulatory molecule in controlling cell fate during TCR/CD28-mediated stimulation was examined. We found that p75-deficient T cells possess a profound defect in IL-2 production in response to TCR/CD28-mediated stimulation. Examination of key signaling intermediates revealed that TCR proximal events such as global tyrosine phosphorylation and ZAP70 phosphorylation, as well as downstream MAPK cascades are unperturbed in p75-deficient T cells. In contrast, p75 is nonredundantly coupled to sustained AKT activity and NF-κB activation in response to TCR/CD28-mediated stimulation. Moreover, p75-deficient T cells possess a defect in survival during the early phase of T cell activation that is correlated with a striking defect in Bcl-xL expression. These data indicate discrete effects of p75 on the intracellular signaling milieu during T cell activation, and reveal the synergistic requirement of TCR, CD28, and p75 toward optimal IL-2 induction and T cell survival. We propose that p75 acts as one of the earliest of the identified costimulatory members of the TNFR family, and is functionally linked to CD28 for initiating and determining T cell fate during activation.

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

“…However, there is accumulating evidence that signaling through the TNF-R2 influences a number of pro-inflammatory responses, including the activation of T cells [16][17][18], myofibroblasts [19], inhibition of angiogenesis and tumor suppression [20].…”

Transgene expression of α tumor necrosis factor with mutations D142N and A144R under control of human telomerase reverse transcriptase promoter eradicates well-established tumors and induces long-term antitumor immunity

“…The proliferative signals are commonly derived from the activation of p75 TNFR. 12,14,15 To assess the proliferative effect of the secreted mutant mTNF-a in transfected tumor cell culture, we performed the in vitro T-cell proliferation assay. As shown in Figure 1a, the control recombinant TNF-a stimulated CTLL-2T cell proliferation in a dosedependent manner.…”

“…[8][9][10] The p55 TNF-a receptor (TNFR) is primarily responsible for signaling in variety of responses including cytotoxicity 11,12 and cytokine secretion, 13 whereas the p75 TNFR is responsible for lymphoproliferative signals and activation of T cells. 12,14,15 To induce high local concentration of TNF-a while limiting systemic use of a high dose of TNF-a, isolated limb perfusion with TNF-a has been applied with less systemic toxicity. 16,17 These results prompted a number of studies aimed at decreasing TNF-a toxicity without modifying its antitumor properties, thereby allowing its use not only for regional treatments but also for systemic therapy.…”

TNFR2 expression on non-bone marrow-derived cells is crucial for lipopolysaccharide-induced septic shock and downregulation of soluble TNFR2 level in serum

“…For example, collecting TNF and ligating it to TNFR1, termed 'ligand passing', 7,11 mediates the anti-tumor effects of TNF when expressed on host innate immune cells, 1 activating different subgroups of T cells during inflammation, tumor growth and autoimmune diseases. [12][13][14][15] Interestingly, TNFR2 expression has also been reported on non-bone marrow (BM)-derived cells, such as vascular endothelial cells. 16 Non-BM TNFR2 expression can function through inhibiting collagen degradation and stimulating the proliferation of intestinal myofibroblasts.…”