scholarly journals HIV disease progression correlates with the generation of dysfunctional naive CD8low T cells

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2189-2199 ◽  
Author(s):  
David Favre ◽  
Cheryl A. Stoddart ◽  
Brinda Emu ◽  
Rebecca Hoh ◽  
Jeffrey N. Martin ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Interferon Α ◽  
Hiv Disease ◽  
Peripheral Blood Mononuclear ◽  
Class I Mhc ◽  
Mhc I

Abstract HIV infection can result in depletion of total CD4+ T cells and naive CD8+ T cells, and in the generation of dysfunctional effector CD8+ T cells. In this study, we show that naive CD8+ T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8low T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8low T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3highCD8+CD4− single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8low T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.

170 Microfluidics cell squeezing enables potent cellular vaccines in murine models through direct cytosolic loading and direct CD8 T cell priming

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A184-A184
Author(s):  
Emrah Ozay ◽  
Matthew Booty ◽  
Katarina Blagovic ◽  
David Soto ◽  
Olivia Pryor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Survival ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Cd8 T Cell ◽  
Laboratory Animals ◽  
Peripheral Blood Mononuclear ◽  
Class I Mhc ◽  
Mhc I

BackgroundThe presentation of sufficient antigen on major histocompatibility complex class I (MHC-I) is essential to prime CD8+ T cells.MethodsTo achieve efficient MHC-I presentation, we used microfluidics cell squeezing (Cell Squeeze®) to deliver antigens directly to the cytosol of antigen presenting cells (APCs), bypassing the need for cross-presentation. In addition to facilitating priming by professional APCs, this approach enables lymphocytic subsets within peripheral blood mononuclear cells (PBMCs) to function as unconventional APCs in mouse preclinical models.ResultsWe demonstrated that microfluidic cell squeezing delivers cargo to major cell populations within splenocytes (T cells, B cells, NK cells, and monocytes) and that protein, peptide, or mRNA antigens are rapidly processed and presented. In vivo, squeezed splenocytes directly presented antigen to CD8+ T cells. In the TC-1 tumor model for HPV+ cancers, squeezed splenocytes completely protect mice when administered prophylactically, protecting 15/15 animals from primary challenge and 11/15 animals from tumor re-challenge. Following therapeutic administration, squeezed splenocytes significantly improved median survival time to 56 days from 28 days, as observed with untreated controls. Immunization can also be combined with chemotherapy to further enhance therapeutic efficacy, improving median survival to over 100 days compared to 81 days with SQZ monotherapy or 32 days with chemotherapy alone. When tumor infiltrating lymphocytes (TILs) were analyzed following therapeutic immunization, squeezed splenocyte immunization elicited a significant influx of antigen specific CD8+ T cells: with SQZ treatment, ~87% of tumor-infiltrating CD8 T cells were antigen-specific, as measured by an E7-tetramer stain, while only ~33.6% and ~1.15% of infiltrating CD8 T cells were specific for E7 with subcutaneous peptide vaccination and no treatment, respectively.ConclusionsThrough the direct cytosolic delivery of antigen, we have engineered unfractionated PBMCs to function as potent APCs. This strategy generates potent antigen-specific CD8+ T cell responses in mouse models. Taken together, these findings support the potential of SQZ-PBMCs as an effective antigen-specific vaccination strategy against cancer. SQZ-PBMC-HPV is currently under clinical evaluation for HPV16+ tumor indications.Ethics ApprovalAll methods were performed in accordance with relevant guidelines and regulations; Animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) at SQZ Biotechnologies, using the recommendations from the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the Office of Laboratory Animal Welfare. All activities were also conducted in accordance with Public Health Service (PHS) Policy on Humane Use and Care of Laboratory Animals.

scholarly journals Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 3873-3880 ◽  
Author(s):  
Lesley White ◽  
Subramaniam Krishnan ◽  
Natasa Strbo ◽  
Huanliang Liu ◽  
Michael A. Kolber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Peripheral Blood Mononuclear ◽  
Perforin Expression

Abstract An urgent need exists to devise strategies to augment antiviral immune responses in patients with HIV who are virologically well controlled and immunologically stable on highly active antiretroviral therapy (HAART). The objective of this study was to compare the immunomodulatory effects of the cytokines interleukin (IL)–21 with IL-15 on CD8 T cells in patients with HIV RNA of less than 50 copies/mL and CD4 counts greater than 200 cells/mm.3 Patient CD8 T cells displayed skewed maturation and decreased perforin expression compared with healthy controls. Culture of freshly isolated patient peripheral-blood mononuclear cells (PBMCs) for 5 hours to 5 days with IL-21 resulted in up-regulation of perforin in CD8 T cells, including memory and effector subsets and virus-specific T cells. IL-21 did not induce T-cell activation or proliferation, nor did it augment T-cell receptor (TCR)–induced degranulation. Treatment of patient PBMCs with IL-15 resulted in induction of perforin in association with lymphocyte proliferation and augmentation of TCR-induced degranulation. Patient CD8 T cells were more responsive to cytokine effects than the cells of healthy volunteers. We conclude that CD8 T cells of patients with HIV can be modulated by IL-21 to increase perforin expression without undergoing overt cellular activation. IL-21 could potentially be useful for its perforin-enhancing properties in anti-HIV immunotherapy.

Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Membrane Filter ◽  
Cd8 T Cell ◽  
Class I ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

scholarly journals Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

2021 ◽  
Author(s):  
L. Sams ◽  
S. Kruger ◽  
V. Heinemann ◽  
D. Bararia ◽  
S. Haebe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Prognostic Information ◽  
Peripheral Blood Mononuclear

Abstract Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

scholarly journals The analysis of the long-term impact of SARS-CoV-2 on the cellular immune system in individuals recovering from COVID-19 reveals a profound NKT cell impairment

2020 ◽  
Author(s):  
jia liu ◽  
Xuecheng Yang ◽  
Hua Wang ◽  
Ziwei Li ◽  
Hui Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Annexin V ◽  
Double Positive ◽  
Peripheral Blood Mononuclear ◽  
Cellular Immune System ◽  
Cellular Immune

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects millions of people and killed hundred-thousands of individuals. While acute and intermediate interactions between SARS-CoV-2 and the immune system have been studied extensively, long-term impacts on the cellular immune system remained to be analyzed. Here, we comprehensively characterized immunological changes in peripheral blood mononuclear cells in 49 COVID-19 convalescent individuals (CI) in comparison to 27 matched SARS-CoV-2 unexposed individuals (UI). Despite recovery from the disease for more than 2 months, CI showed significant decreases in frequencies of invariant NKT and NKT-like cells compared to UI. Concomitant with the decrease in NKT-like cells, an increase in the percentage of Annexin V and 7-AAD double positive NKT-like cells was detected, suggesting that the reduction in NKT-like cells results from cell death months after recovery. Significant increases in regulatory T cell frequencies, TIM-3 expression on CD4 and CD8 T cells, as well as PD-L1 expression on B cells were also observed in CI, while the cytotoxic potential of T cells and NKT-like cells, defined by GzmB expression, was significantly diminished. However, both CD4 and CD8 T cells of CI showed increased Ki67 expression and were fully capable to proliferate and produce effector cytokines upon TCR stimulation. Collectively, we provide the first comprehensive characterization of immune signatures in patients recovering from SARS-CoV-2 infection, suggesting that the cellular immune system of COVID-19 patients is still under a sustained influence even months after the recovery from disease.

scholarly journals Cloning and Expression of the Tibetan Pig Interleukin-23 Gene and Its Promotion of Immunity of Pigs to PCV2 Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 250
Author(s):  
Yongle Xiao ◽  
Huan Zhang ◽  
Jianlin Chen ◽  
Yi Chen ◽  
Jinghai Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
B Cell Lymphoma ◽  
Cloning And Expression ◽  
Porcine Circovirus ◽  
Peripheral Blood Mononuclear ◽  
Pcv2 Vaccine ◽  
Interleukin 23

Vaccines against Porcine circovirus type 2 (PCV2) have been studied intensely and found to be effective in decreasing mortality and improving growth in swine populations. In this study, interleukin-23 (IL-23) gene was cloned from peripheral blood mononuclear cells (PBMCs) of Tibetan pigs and inserted into a eukaryotic VR1020 expression vector-VRIL23. Coated with chitosan (CS), the VRIL23-CS was intramuscularly injected into 3-week-old piglets with PCV2 vaccine. The blood was collected after vaccination at 0, 1, 2, 4, 8, and 12 weeks, respectively, to detect the immunological changes. The IgG2a and specific PCV2 antibodies were detected using ELISA, and blood CD4+ and CD8+ T cells were quantified by flow cytometry. Quantitative fluorescence PCR was used to evaluate the expression of immune genes. The results indicate that leukocytes, erythrocytes, and CD4+ and CD8+ T cells increased significantly in the blood of VRIL23-CS inoculated piglets in comparison with the control (p < 0.05) and so did the IgG2a and PCV2 antibodies. In addition, the expressions of Toll-like receptor (TLR) 2, TLR7, cluster of differentiation (CD) 45, IL-15, IL-12, signal transducer and activator of transcription (STAT)1, STAT2, STAT3, STAT4, and B-cell lymphoma (Bcl)-2 genes were also obviously higher in the VRIL23-CS inoculated pigs at different time points (p < 0.05). Overall, the results demonstrated that VRIL23-CS can enhance the comprehensive immune responses to PCV2 vaccine in vivo and has the promising potential to be developed into a safe and effective adjuvant to promote the immunity of pig against PCV disease.

scholarly journals IMMU-18. IMMUNOGENOMIC RESPONDER PHENOTYPE FROM A PHASE I TRIAL OF ANTI-LAG3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi122-vi123
Author(s):  
Christina Jackson ◽  
John Choi ◽  
JiaJia Zhang ◽  
Anna Piotrowski ◽  
Tobias Walbert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Lower Percentage ◽  
Radiographic Evaluation ◽  
Peripheral Blood Mononuclear ◽  
Initial Resection

Abstract BACKGROUND Immune checkpoint inhibitors (ICIs) are not uniformly effective in glioblastoma treatment. Immunogenomic determinants may identify patients who are most likely to benefit from these therapies. Therefore, we compared the immunogenomic phenotype of a responder to combination anti-LAG-3 and anti-PD-1 therapy to non-responders. METHODS We performed T cell receptor (TCR) sequencing and gene expression analysis on pre-treatment, post-chemoradiation, and post-immunotherapy tumor specimens of glioblastoma patients treated with anti-LAG3 in combination with anti-PD-1 after first recurrence (NCT02658981, ongoing). We evaluated T cell clonotypes and immunophenotype of serially collected peripheral blood mononuclear cells (PBMCs) during treatment using multi-parametric flow cytometry. RESULTS To date, six patients have been enrolled in the initial anti-LAG-3 and anti-PD-1 cohort. One patient demonstrated complete response, one had stable disease, and four had progressive disease by radiographic evaluation. The responder demonstrated substantially higher TCR clonality in the resected tumor at initial diagnosis compared to non-responders (mean 0.028 vs. 0.005). Shared tumor infiltrating clonotypes with pre-immunotherapy PBMCs exhibited an increase in frequency from initial resection (6.8%) to resection at recurrence (20%). The responder’s tumor at initial resection exhibited increased gene signatures of PD1low CD8+ T cells, chemokine signaling, and interferon gamma pathways. On PBMC phenotypic analysis, the responder demonstrated significantly higher percentages of CD137+ CD8+T cells (median 8.38% vs 3.24%, p=0.02) and lower percentages of Foxp3+CD137+ CD4+T cells compared to non-responders (median 18.5% vs. 38.5%, p=0.006). Interestingly, dynamic analysis of PBMCs showed that the responder demonstrated a lower percentage of PD1+ CD8+ T cells pre-immunotherapy (median 2.5% vs.12.4%, p=0.002), with persistent decrease over the course of treatment while non-responders showed no consistent pattern. CONCLUSION Our preliminary results demonstrate significant differences in tumor and peripheral blood immunogenomic characteristics between responder and non-responders to anti-LAG3 and anti-PD-1 therapy. These immunogenomic characteristics may help stratify patients’ response to combination ICIs.

Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3161-3170 ◽  
Author(s):  
Uri Lopatin ◽  
Xu Yao ◽  
Richard K. Williams ◽  
Jack J. H. Bleesing ◽  
Janet K. Dale ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Messenger Rna ◽  
Mononuclear Cells ◽  
Population Expansion ◽  
Interleukin 10 ◽  
Lymphoid Tissues ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Peripheral Blood Mononuclear ◽  
Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P &lt; .001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA;P &lt; .001 and P &lt; .01, respectively). By fractionating PBMC populations, disproportionately high concentrations of IL-10 mRNA were found in the CD4−CD8−T-cell population, expansion of which is virtually pathognomonic for ALPS. Immunohistochemical staining showed intense IL-10 protein signals in lymph node regions known to contain CD4−CD8− T cells. Nonetheless, in vitro studies showed no influence of IL-10 on the survival of CD4−CD8− T cells. Overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS.

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