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CD8 downregulation is an overlooked component of self-reactive CD8+ T cell tolerance. CD8 downregulation is accompanied by T cell inhibition at the signaling and transcriptional levels. Loss of CD8 expression impairs the capacity of T cells to engage peptide-major histocompatibility complex complexes. CD8 downregulation may be a temporary event, as cells may regain CD8 expression and effector function. CD8 downregulation in mammals may be a part of a multilayered mechanism that inactivates self-reactive CD8+ T cells. Loss of CD8 may impair their capacity to engage target cells, while other simultaneous changes curb their activation and effector functions. Understanding this process represents a central element in our interpretation of CD8+ T cell physiology and its role in autoimmune diseases and cancer immunology. Activated CD8+ T cells directly kill target cells. Therefore, the regulation of their function is central to avoiding immunopathology. Mechanisms that curb effector functions in CD4+ and CD8+ T cells are mostly shared, yet important differences occur. Here, we focus on the control of CD8+ T cell activity and discuss the importance of a poorly understood aspect of tolerance that directly impairs engagement of target cells: the downregulation of CD8. We contextualize this process and propose that it represents a key element during CD8+ T cell modulation. [ABSTRACT FROM AUTHOR]

Our previous study found that double negative T cells (DNTs) could promote the NLRP3 activation through high expression of TNF‐α, thereby leading to hepatic fibrosis progression. We focused on investigating the role and mechanism of DNTs in regulating the Th9 cells differentiation in liver fibrosis. In our results, among patients with liver fibrosis, the proportions of peripheral blood DNTs and Th9 cells were up‐regulated and positively correlated. While promoting the progression of liver fibrosis in mice, DNTs could elevate the proportion of Th9 cells and activate the TNFR2‐STAT5‐NF‐κB pathway. The use of IL‐9 and TNF‐α monoclonal antibodies (mAbs) inhibited the effect of DNTs and lowered the proportion of Th9 cells in tissues. In vitro experiments showed that DNTs could promote the Th9 cells differentiation of Naive T cells, while TNF‐α mAbs could inhibit such effect of DNTs to lower the proportion of Th9 cells. We found that DNTs can activate TNFR2‐STAT5‐NF‐κB pathway by secreting TNF‐α, thereby promoting the Th9 Cells differentiation to facilitate the progression of liver fibrosis. There is interaction between DNTs and Th9 cells. [ABSTRACT FROM AUTHOR]

Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/ lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings. [ABSTRACT FROM AUTHOR]

Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.

• The proportion of TCR-αβ+ DNTs was elevated in patients with aAA than HD. • SAA/VSAA patient with CR after IST had higher proportion of TCR-αβ+ DNTs at diagnosis. • Higher proportion of TCR-αβ+ DNTs at diagnosis implied a good response to IST. The pathophysiology of acquired aplastic anemia (aAA) is most associated with T cell mediated immune dysfunction, but the role of CD4- CD8- double negative T cells (DNTs) in pediatric patients with aAA is unclear. In this study, we aimed to investigate the proportion of TCR-αβ+ DNTs in pediatric patients with aAA and correlation with the response to immunosuppressive therapy (IST). Assessment of DNTs from peripheral blood was done by sensitive multi-color flow cytometry. The potential clinical value of TCR-αβ+ DNTs was then assessed by the receiver operating characteristic (ROC) curves. The retrospective study evaluated 164 pediatric patients with aAA and 105 healthy donors (HD). Our data showed higher proportion of TCR-αβ+ DNTs in total lymphocytes [1.04% (0.79%-1.40%) vs 0.69% (0.47%-0.87%), p < 0.001] and CD3+ T cells [1.52% (1.10%-1.96%) vs 1.10% (0.70%-1.40%), p < 0.001] in aAA compared to HD. Patients with SAA/VSAA achieving complete response (CR) after IST had a higher proportion of TCR-αβ+ DNTs at initial diagnosis, than those not achieving CR for total (1.21%±0.39 vs 0.78%±0.38, p < 0.05) and CD3+ T cells (1.74%±0.53 vs 1.15%±0.59, p < 0.05). The ROC analysis showed areas under the curves (AUCs) for TCR-αβ+ DNT proportion in lymphocytes and CD3+ T cells were 0.756 (cutoff value 1.33, p < 0.05) and 0.758 (cutoff value 1.38, p < 0.05), respectively. And the complete response rate was higher in TCR-αβ+ DNT proportion high group than in TCR-αβ+ DNT proportion low group at baseline (p < 0.001). Our observations suggest that elevated TCR-αβ+ DNTs seems to play a role in the pathogenesis of aAA, and it was involve in immune response to IST. [ABSTRACT FROM AUTHOR]