Tumor-infiltrating lymphocytes in ipsilateral breast tumor recurrences predict prognosis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 546-546
Author(s):  
Axel Stenmark Tullberg ◽  
Emma Nimeus-Malmström ◽  
Fredrika Killander ◽  
Martin Sjöström ◽  
Henri A.J. Puttonen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Distant Metastasis ◽  
Breast Tumor ◽  
Memory T Cells ◽  
Effector Memory ◽  
Matched Pairs ◽  
Ipsilateral Breast ◽  
Gene Expression Analyses

546 Background: The antitumoral immune response is dynamic and changes with tumor progression. Previous studies show that immunohistochemical (IHC) assessment of TILs in local recurrences can predict prognosis. It is not clear how adjuvant radiotherapy (RT) can alter the local immune response or if gene expression analyses of TILs in recurrences can provide prognostic information. Methods: Matched biopsies from primary tumors and ipsilateral breast tumor recurrences (IBTRs) from the randomized SweBCG91RT trial were assessed for TILs. Analyses were performed using gene expression (86 matched pairs) and IHC assessment (126 matched pairs). Results: The median time to IBTR was 8.0 years among irradiated patients and 3.6 years among unirradiated patients. In the gene expression analyses, higher absolute values of CD8+ T cells, CD4+ effector memory and CD8+ effector memory T cells in the recurrence could significantly predict a decreased risk of subsequent distant metastasis. In addition, a net increase of these cells in the IBTR compared to the primary tumor was associated with a significantly lower risk of metastasis. TILs did not change significantly between the matched tumors for the whole group or among irradiated patients versus unirradiated patients in the gene expression or IHC analyses. Surprisingly, the group with unchanged TILs levels as measured by IHC had the lowest risk of metastasis while an increase or a decrease in TILs was significantly associated with an increased risk. Conclusions: Cytotoxic and memory T cells in the recurrence protect against subsequent distant metastasis although IHC measurement of TILs could not confirm these results. No significant differences in TILs infiltration between irradiated versus unirradiated patients could be determined in the recurrences. Further analyses including changes of subtypes between the primary tumor and the recurrence will be presented.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

scholarly journals Contribution of Resident Memory CD8+ T Cells to Protective Immunity Against Respiratory Syncytial Virus and Their Impact on Vaccine Design

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 147 ◽  
Author(s):  
Retamal-Díaz ◽  
Covián ◽  
Pacheco ◽  
Castiglione-Matamala ◽  
Bueno ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Respiratory Syncytial Virus ◽  
Viral Infections ◽  
Memory T Cells ◽  
Effector Memory ◽  
Memory Cells ◽  
Effective Immune Response ◽  
Syncytial Virus ◽  
Tract Infections

Worldwide, human respiratory syncytial virus (RSV) is the most common etiological agent for acute lower respiratory tract infections (ALRI). RSV-ALRI is the major cause of hospital admissions in young children, and it can cause in-hospital deaths in children younger than six months old. Therefore, RSV remains one of the pathogens deemed most important for the generation of a vaccine. On the other hand, the effectiveness of a vaccine depends on the development of immunological memory against the pathogenic agent of interest. This memory is achieved by long-lived memory T cells, based on the establishment of an effective immune response to viral infections when subsequent exposures to the pathogen take place. Memory T cells can be classified into three subsets according to their expression of lymphoid homing receptors: central memory cells (TCM), effector memory cells (TEM) and resident memory T cells (TRM). The latter subset consists of cells that are permanently found in non-lymphoid tissues and are capable of recognizing antigens and mounting an effective immune response at those sites. TRM cells activate both innate and adaptive immune responses, thus establishing a robust and rapid response characterized by the production of large amounts of effector molecules. TRM cells can also recognize antigenically unrelated pathogens and trigger an innate-like alarm with the recruitment of other immune cells. It is noteworthy that this rapid and effective immune response induced by TRM cells make these cells an interesting aim in the design of vaccination strategies in order to establish TRM cell populations to prevent respiratory infectious diseases. Here, we discuss the biogenesis of TRM cells, their contribution to the resolution of respiratory viral infections and the induction of TRM cells, which should be considered for the rational design of new vaccines against RSV.

Unique gene expression program of human germinal center T helper cells

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1952-1960 ◽  
Author(s):  
Chang H. Kim ◽  
Hyung W. Lim ◽  
Jong R. Kim ◽  
Lusijah Rott ◽  
Peter Hillsamer ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Germinal Center ◽  
Memory T Cells ◽  
Effector Memory ◽  
T Helper ◽  
Th Cells ◽  
Effector Memory T Cells ◽  
Expression Program

Abstract Gene expression profiling was used to compare the gene expression patterns of human germinal center (GC) T helper (Th) cells with other CD4+ T-cell subsets (naive, central, and effector memory T cells). GC-Th cells, specifically localized in germinal centers to help B cells, are distantly related to central and effector memory T cells in global gene expression profiles. GC-Th cells displayed substantial differences in mRNA for adhesion molecules, chemoattractant receptors, and cytokines compared with other populations. Distinct expression of transcriptional factors by GC-Th cells is consistent with the hypothesis that they may be different from other T cells in cell lineage. Interestingly, CXCL13, a critical chemokine for B-cell entry to lymphoid follicles, is one of the most highly up-regulated genes in GC-Th cells. GC-Th cells (but not other T cells) produce and secrete large amounts of functional CXCL13 upon T-cell receptor activation, a process that is dependent on costimulation, requires translation and transcription, and is dramatically enhanced by activation in the presence of GC-B cells. This study revealed for the first time the unique gene expression program of GC-Th cells.

scholarly journals Chimeric Vaccines Designed by Immunoinformatics-Activated Polyfunctional and Memory T Cells That Trigger Protection against Experimental Visceral Leishmaniasis

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 252 ◽  
Author(s):  
Rory Cristiane Fortes De Brito ◽  
Jeronimo Conceição Ruiz ◽  
Jamille Mirelle de Oliveira Cardoso ◽  
Thais Lopes Valentim Di Paschoale Ostolin ◽  
Levi Eduardo Soares Reis ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Visceral Leishmaniasis ◽  
Vaccine Development ◽  
Memory T Cells ◽  
Parasite Burden ◽  
Effector Memory ◽  
Potential Candidate ◽  
Protective Mechanisms ◽  
Strong Immune Response

Many vaccine candidates against visceral leishmaniasis (VL) have been proposed; however, to date, none of them have been efficacious for the human or canine disease. On this basis, the design of leishmaniasis vaccines has been constantly changing, and the use of approaches to select specific epitopes seems to be crucial in this scenario. The ability to predict T cell-specific epitopes makes immunoinformatics an even more necessary approach, as in VL an efficient immune response against the parasite is triggered by T lymphocytes in response to Leishmania spp. immunogenic antigens. Moreover, the success of vaccines depends on the capacity to generate long-lasting memory and polyfunctional cells that are able to eliminate the parasite. In this sense, our study used a combination of different approaches to develop potential chimera candidate vaccines against VL. The first point was to identify the most immunogenic epitopes of Leishmania infantum proteins and construct chimeras composed of Major histocompatibility complex (MHC) class I and II epitopes. For this, we used immunoinformatics features. Following this, we validated these chimeras in a murine model in a thorough memory study and multifunctionality of T cells that contribute to a better elucidation of the immunological protective mechanisms of polyepitope vaccines (chimera A and B) using multicolor flow cytometry. Our results showed that in silico-designed chimeras can elicit polyfunctional T cells producing T helper (Th)1 cytokines, a strong immune response against Leishmania antigen, and the generation of central and effector memory T cells in the spleen cells of vaccinated animals that was able to reduce the parasite burden in this organ. These findings contribute two potential candidate vaccines against VL that can be used in further studies, and help in this complex field of vaccine development against this challenging parasite.

scholarly journals Exploring inflammatory signatures in arthritic joint biopsies with Spatial Transcriptomics

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Konstantin Carlberg ◽  
Marina Korotkova ◽  
Ludvig Larsson ◽  
Anca I. Catrina ◽  
Patrik L. Ståhl ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Immune Cell ◽  
Memory T Cells ◽  
Inflammatory Diseases ◽  
Adaptive Immune Response ◽  
Cell Types ◽  
Effector Memory ◽  
Cellular Mechanisms ◽  
Chronic Inflammatory Diseases

AbstractLately it has become possible to analyze transcriptomic profiles in tissue sections with retained cellular context. We aimed to explore synovial biopsies from rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients, using Spatial Transcriptomics (ST) as a proof of principle approach for unbiased mRNA studies at the site of inflammation in these chronic inflammatory diseases. Synovial tissue biopsies from affected joints were studied with ST. The transcriptome data was subjected to differential gene expression analysis (DEA), pathway analysis, immune cell type identification using Xcell analysis and validation with immunohistochemistry (IHC). The ST technology allows selective analyses on areas of interest, thus we analyzed morphologically distinct areas of mononuclear cell infiltrates. The top differentially expressed genes revealed an adaptive immune response profile and T-B cell interactions in RA, while in SpA, the profiles implicate functions associated with tissue repair. With spatially resolved gene expression data, overlaid on high-resolution histological images, we digitally portrayed pre-selected cell types in silico. The RA displayed an overrepresentation of central memory T cells, while in SpA effector memory T cells were most prominent. Consequently, ST allows for deeper understanding of cellular mechanisms and diversity in tissues from chronic inflammatory diseases.

scholarly journals Lung memory T-cell response in mice following intranasal immunization with influenza vector expressing mycobacterial proteins

2020 ◽  
Vol 10 (3) ◽  
pp. 506-514
Author(s):  
A.-P. S. Shurygina ◽  
N. V. Zabolotnykh ◽  
T. I. Vinogradova ◽  
K. A. Vasilyev ◽  
Zh. V. Buzitskaya ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Vaccine Candidate ◽  
Memory T Cells ◽  
Bcg Vaccine ◽  
Tuberculosis Infection ◽  
Effector Memory ◽  
Intranasal Immunization ◽  
Boost Vaccination

Improving specific prevention of tuberculosis continues to be a top priority in phthisiology. “Prime-boost” vaccination schemes aim to maintain adequate levels of specific immunity while forming long-term protection. They are based on sequential use of BCG vaccine and new vaccine candidates expressing protective mycobacterial proteins. The development of new tuberculosis prevention approaches requires an understanding of how the anti-tuberculosis immune response forms and which mechanisms provide TB protection. Since tuberculosis is an airborne infection, vaccine effectiveness largely depends on mucosal immunity based on the formation of long-lived, functionally-active memory T-lymphocytes in the respiratory tract. We have previously shown that the influenza vector expressing ESAT-6 and Ag85A mycobacterial proteins (Flu/ESAT-6_Ag85A) in vaccination scheme of intranasal boost immunization resulted in significant increase of BCG's protective effect according to key indicators aggregate data in experimental tuberculosis infection. The aim of this work was to study the effect of intranasal immunization with the Flu/ESAT-6_Ag85A influenza vector on the formation of antigen-specific central and effector memory T cells and the cytokine-producing activity of effector T cells (TEM) in BCG standard and “BCG prime — influenza vector boost” vaccination schemes in mice. Intranasal immunization with the influenza vector has been shown to increase the proportion of antigen-specific CD4+ central memory T cells (TCM) in the pool of activated lymphocytes of lung and spleen reaching significant differences from the BCG group in the percentage of spleen CD4+ TCM (p < 0.01). In contrast to BCG, vaccination with the studied vaccine candidate was accompanied by accumulation of highly differentiated CD8 effector cells in lung, the target organ during tuberculosis infection. Comparative evaluation of the cell-mediated, post-vaccine immune response after immunization with influenzavector-based vaccine candidate (intranasal/mucosal) or BCG vaccine (subcutaneous) showed advantages in the mucosal group: in formation of functionally active subpopulations of effector CD4 and CD8 T lymphocytes (CD44highCD62Llow) in lungs secreting IL-2 as well as polyfunctional cells capable of coproducing two cytokines (IFNγ/TNFα or IFNγ/IL-2) or three cytokines (IFNγ/TNFα/IL-2). Due to their more pronounced effector function, polyfunctional T-lymphocytes can be considered to be potential immunological markers of protective immunity in tuberculosis.

scholarly journals Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation

2021 ◽  
Author(s):  
Blagoje Soskic ◽  
Eddie Cano-Gamez ◽  
Deborah J. Smyth ◽  
Kirsty Ambridge ◽  
Ziying Ke ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Memory T Cells ◽  
Disease Risk ◽  
Effector Memory ◽  
Immune Disease ◽  
Time Points

AbstractDuring activation, T cells undergo extensive changes in gene expression which shape the properties of cells to exert their effector function. Therefore, understanding the genetic regulation of gene expression during T cell activation provides essential insights into how genetic variants influence the response to infections and immune diseases. We generated a single-cell map of expression quantitative trait loci (eQTL) across a T cell activation time-course. We profiled 655,349 CD4+ naive and memory T cells, capturing transcriptional states of unstimulated cells and three time points of cell activation in 119 healthy individuals. We identified 38 cell clusters, including stable clusters such as central and effector memory T cells and transient clusters that were only present at individual time points of activation, such as interferon-responding cells. We mapped eQTLs using a T cell activation trajectory and identified 6,407 eQTL genes, of which a third (2,265 genes) were dynamically regulated during T cell activation. We integrated this information with GWAS variants for immune-mediated diseases and observed 127 colocalizations, with significant enrichment in dynamic eQTLs. Immune disease loci colocalized with genes that are involved in the regulation of T cell activation, and genes with similar functions tended to be perturbed in the same direction by disease risk alleles. Our results emphasize the importance of mapping context-specific gene expression regulation, provide insights into the mechanisms of genetic susceptibility of immune diseases, and help prioritize new therapeutic targets.

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