Search

Programmed death-1 (PD-1), a key immune checkpoint molecule, has been developed as an oncotherapy target for various carcinomas. However, treatment with anti-PD-1 elicited only a minimal effect in pancreatic ductal adenocarcinoma (PDAC). Subsequent studies revealed the existence of a subset of PD-1+ T cells coexpressing CD38 and CD101, representing a fixed dysfunctional subpopulation that are not able to be rescued by anti-PD-1 immunotherapy. However, whether this subpopulation of PD-1 expressing CD8+ T cells could be useful in predicting PDAC stage or prognosing survival is unknown. In this study, we used flow cytometry and immunofluorescence assay to analyze the expression of CD38 and CD101 in 183 clinical PDAC samples, including 84 of peripheral blood and 99 of surgical tissues. High coexpression of CD38/CD101 on peripheral PD-1+CD8+ T cells or tumor-infiltrating lymphocytes (TILs) was found to be most significantly correlated with Tumor/Node/Metastasis (T/N/M) classification and clinical stage, in contrast PD-1+CD8+ T cells could not correlate with T classification. CD38/CD101 co-repression on TILs also correlated with the poor survival in these PDAC patient samples. Our data suggest that CD38/CD101 might represent a more helpful biomarker than PD-1 alone for diagnosis and prognosis of PDAC. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Genome-wide analyses have revealed that interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with susceptibility to SLE. Our previous study investigated the role of IRAK1 in nuclear factor-κB (NF-κB)-related pathways in a mouse model of lupus. In this study, we aimed to further explore the etiological role of IRAK1. The gene expression and phosphorylation of IRAK1 in CD4+ T cells from lupus patients and healthy controls were examined by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively. The percentage of circulating Th17 cells and plasma IL-17A levels were evaluated by flow cytometry and enzyme-linked immunosorbent assay, respectively. The influence of IRAK1 suppression on Th17 development was assessed using an IRAK1 inhibitor and small interfering RNA. We found that IRAK1 transcript levels in CD4+ T cells were significantly upregulated in SLE patients in comparison to controls and were positively correlated with disease activity. In vitro experiments showed that lupus CD4+ T cells had more pronounced IRAK1 phosphorylation at threonine-209 upon IL-1β stimulation than did control cells. Moreover, IRAK1 expression was positively associated with Th17/IL-17A in patients. When naïve CD4+ T cells were polarized toward the Th17 subset, IRAK1 inhibition significantly repressed IL-17A production and the gene expression of Th17 markers, namely, retinoic acid receptor-related orphan receptor c, IL-23 receptor and IL-17A. In summary, IRAK1 is overexpressed and hyperactivated in CD4+ T cells from SLE patients. IRAK1 inhibition attenuates Th17 differentiation in the context of human SLE, suggesting a therapeutic opportunity. [ABSTRACT FROM AUTHOR]

CD8+CD62L+ T cells have been shown to play pivotal roles in anti-viral immunity, chronic myeloid leukemia and renal cell carcinoma. Recently, CD8+CD62L+ T cells from naïve mice (nCD8+CD62L+ T cells) have shown superior anti-tumor properties in melanoma-bearing mice. Considering that antigen-specific memory T cells have shown to possess more potent immunity than non-specific memory T cells, we hypothesized that CD8+CD62L+ T cells from tumor-bearing individuals (mCD8+CD62L+ T cells) might have superior anti-tumor effect than nCD8+CD62L+ T cells. Therefore, we investigated phenotypes, functions and the in vivo distribution of mCD8+CD62L+ T cells in tumor-bearing mice. We found that, while keeping the features of central memory T cells, the frequency of mCD8+CD62L+ T cell in the spleen of tumor-bearing mice was significantly higher than that the one of nCD8+CD62L+ T cell in naive mice. Moreover, we demonstrated that mCD8+CD62L+ T cells had higher proliferation rate and IFN-γ production than nCD8+CD62L+ T cells, in vitro. We performed adoptive transfer of mCD8+CD62L+ T cells into melanoma-bearing mice and tracked them in spleen, lymph nodes and in melanoma tissues. Our results show that mCD8+CD62L+ T cells had stronger in vivo anti-tumoral activity than nCD8+CD62L+ T cells. This study highlights the therapeutic potential of mCD8+CD62L+ T cells in the immunotherapy of melanoma and possibly other tumors. [ABSTRACT FROM AUTHOR]

Folate receptor 4 (FR4) is recently found as a lymphoid tissue specific protein. In this study, we have identified an alternative splicing variant of the FR4 gene from murine splenocytes, termed FR4v, which is almost identical to FR4 cDNA sequence except with the retained 108 bp intron 3 between exon 3 and 4 of FR4 gene. FR4v mRNA encodes a larger protein than FR4 and is constitutively expressed on CD4+CD25+ regulatory T cell (Treg) membrane via a GPI anchor mechanism. Whether FR4v plays a redundant or unique functional role in Tregs should be investigated further in the future. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B was characterized by fluctuant immune response to infected hepatocytes resulting in hepatic inflammation and virus persistence. Recently, Programmed Death-1 (PD-1) and its ligand PD-L1 have been demonstrated to play an essential role in balancing antiviral immunity and inflammation in the livers of acute hepatitis B patients, significantly influencing disease outcome. PD-1 up-regulation in peripheral T cells is associated with immune dysfunction in chronic hepatitis B patients. However, the effect of PD-1/PD-L1 on hepatic damage and chronic infective status is still unknown in patients with chronic HBV infection. Here, we report up-regulation of PD-1 and PD-L1 in liver biopsies from 32 chronic HBV patients compared to 4 healthy donors. PD-1/PD-L1 up-regulation was significantly associated with hepatic inflammation and ALT elevation. Moreover, appropriate up-regulation but not overexpression of PD-L1 in the active phase of chronic hepatitis B as well as lower expression of PD-L1 in the inactive phase in liver residential antigen presenting cells (including Kupffer cells and sinusoidal endothelial cells) may contribute to viral inhibition. Our data suggest that the intrahepatic interaction of PD-1 and PD-L1 might play an important role in balancing the immune response to HBV and immune-mediated liver damage in chronic HBV infection. [ABSTRACT FROM AUTHOR]

Expanded CD4+CD28null T cells have not been described in the circulation of patients with chronic hepatitis B (CHB). The aim of the present was to detect and characterize the surface phenotype and functional capacity of these cells in CHB patients. Expanded CD4+CD28null T cells were detected in the circulation of CHB patients with high viral load and elevated aminotransferase levels. Most CD4+CD28null T cells showed a CD27-CD45RA-CD45RO+ surface phenotype. The markers CD56, CD57 and killer immunoglobulin-like receptor (KIR) were detected on CD4+CD28null T cells, but the majority were positive for CD57. Functionally, CD4+CD28null T cells were found to be potent cytotoxic T lymphocytes with perforin and granzyme B secretion profiles. These findings indicate that the expanded CD4+CD28null T cells are cytotoxic memory T cells and display a distinct functional phenotype in comparison with CD4+CD28+ T cells. The presence of these cells appears to be associated with inflammatory conditions, suggesting that these elevated CD4+CD28null T cells might be involved in the pathogenesis of CHB. [ABSTRACT FROM AUTHOR]