In summary, our results show that Treg-mediated suppression of T cell proliferation, especially that of CD8 T cells is nearly ablated in the presence of IL-12. IL-12 induces IFN-c expression by Tregs, but this does not affect Treg immunosuppressive function. Rather, the ability of IL-12 to reverse Treg immunosuppression results, at least in part, from effects on IL-2 and IL-2R expression and by extension, differential IL-2 signaling in mixed cultures of lymphocytes. Genetic Variation in the TNF Gene Is Associated with Susceptibility to Severe Sepsis, but Not with Mortality BACKGROUND: Tumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-α (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS: Ten SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (P(adj) = 0.00046, odds ratio (OR)(adj) = 1.92) and sepsis patients (P(adj) = 0.002, OR(adj) = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (P(adj) = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis. CONCLUSIONS/SIGNIFICANCE: Our findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population. Sepsis is an infection-initiated and inflammation-induced syndrome. Despite progress in the development of antibiotics and other supportive care therapies, severe sepsis remains an unconquered challenge for the clinicians with an unacceptable high mortality rate of 30%-50% [1] . The response to infection is diverse among different individuals. Given the same therapies, most sepsis patients will recover and do well, while a small, but significant portion, will develop severe sepsis and multiple organ system failure, refractory hypotension and death [2, 3] . Currently, more and more evidence showed that genetic factors played an important role in the development and severity of sepsis [4, 5, 6, 7, 8, 9, 10, 11] . Common sequence variants within genes involved in pro-inflammatory response have received particular attention [12, 13] .