CD8+ T cells in tumor parenchyma and stroma by image analysis (IA) and gene expression profiling (GEP): Potential biomarkers for immuno-oncology (I-O) therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2594-2594
Author(s):  
Peter M Szabo ◽  
George Lee ◽  
Scott Ely ◽  
Vipul Baxi ◽  
Harsha Pokkalla ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumor Biology ◽  
Geographical Location ◽  
Cd8 T Cell ◽  
Invasive Margin ◽  
Potential Biomarker ◽  
Tumor Parenchyma

2594 Background: Distribution patterns of CD8+ T cells within the tumor microenvironment (TME) can be assessed by IA, which may reflect underlying tumor biology and serve as a potential biomarker to assess the utility of I-O therapy. These patterns are variable and may be classified as immune desert (minimal infiltrate), excluded (T cells confined to tumor stroma or to the invasive margin), or inflamed (T cells diffusely infiltrating tumor parenchyma and stroma). We hypothesized that association of a GEP signature with abundance of parenchymal and stromal T-cell infiltrates may identify biomarkers of response or resistance to I-O therapy. To test this, we applied an AI-powered IA platform to quantify CD8+ T cells by geographical location and used GEP to define both CD8 abundance and associated geographic localization to tumor parenchyma and stroma. Methods: We performed an analysis using a tumor inflammatory GEP assay and CD8 immunohistochemistry on procured specimens (335 melanoma, 391 SCCHN). Digitized slides were used to train a convolutional neural network to quantify the number of CD8+ T cells in stroma, tumor parenchyma, parenchyma-stromal interface, and invasive margin. Generalized constrained regression models were used to predict GEP signatures specifically for stromal and parenchymal CD8+ T cells. Results: Parenchymal and stromal GEP scores were highly concordant with CD8+ infiltrate geography (adj- r2: 0.67, 0.65, respectively; P ≤ 0.01). Little overlap existed between gene sets associated with parenchymal and stromal CD8 T-cell geographies. CSF1R and NECTIN2 gene expression was observed to correlate inversely with parenchymal localization and directly with stromal CD8+ T-cell abundance. Conclusions: GEP signatures can be identified that are concordant with various CD8+ T-cell localization patterns in melanoma and SCCHN, demonstrating that GEP-IA can be developed to identify the immune status of interest in the TME. The specific genes identified have potential to elucidate mechanisms of resistance and/or inform I-O targets that can be further evaluated in relation to clinical significance in future studies.

WT1-Specific CD8+ T Lymphocytes May Participate in the Elimination of Acute Lymphoblastic Leukemia Following Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3679-3679 ◽  
Author(s):  
Katayoun Rezvani ◽  
Agnes Yong ◽  
Stephan Mielke ◽  
Bipin N. Savani ◽  
David A. Price ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Lymphoblastic Leukemia ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Wt1 Gene ◽  
Cell Responses

Abstract There is clinical evidence that a graft-versus-leukemia (GVL) effect occurs following allogeneic stem cell transplantation for acute lymphoblastic leukemia (ALL). However, the potency of this GVL effect is often associated with unwanted graft-versus-host-disease (GVHD) and disease relapse remains a major contributor to treatment failure. Wilms’ tumor gene 1 (WT1) is overexpressed in 70–90% of cases of ALL and has been identified as a convenient minimal residual disease (MRD) marker. WT1 is an attractive immunotherapeutic target in ALL because peptides derived from WT1 can induce CD8+ T-cell responses, and being non-allelic, WT1 would be unlikely to provoke GVHD. We investigated whether CD8+ T-cells directed against an HLA-A*0201 restricted epitope of WT1 (WT126) occur in ALL patients during the early phase of immune reconstitution post-SCT (days 30–180). We analyzed CD8+ T-cell responses against WT1 in 10 HLA-A*0201+ ALL SCT recipients and their respective donors using WT1/HLA-A*0201 tetrameric complexes and flow cytometry for intracellular IFN-gamma. We studied the kinetics WT1-specific CD8+ T-cell responses in consecutive samples obtained post-SCT. CD8+ T-cells recognizing WT1 were detected ex vivo in samples from 5 of 10 ALL patients post-SCT but not in patients pre-SCT. WT1-tetramer+ CD8+ T cells had a predominantly effector memory phenotype (CD45RO+CD27−CD57+). WT1 gene expression in pre-SCT and donor samples was assayed by quantitative real-time PCR (RQ-PCR). WT1 expression in PBMC from healthy donors was significantly lower than in patients (median 0, range 0–66 ×10−4 WT1/ABL compared to patients, median 12, range 0–2275 ×10−4 WT1/ABL) (P < 0.01). There was a strong correlation between the emergence of WT1-specific CD8+ T cells and a reduction in WT1 gene expression (P < 0.001) (as depicted below) suggesting direct anti-ALL activity post-SCT. Disappearance of WT1-specific CD8+ T-cells from the blood coincided with reappearance of WT1 gene transcripts, consistent with a molecular relapse, further supporting the direct involvement of WT1-specific CD8+ T-cells in the GVL response. These results provide evidence for the first time of spontaneous T-cell reactivity against a leukemia antigen in ALL patients. Our results support the immunogenicity of WT1 in ALL patients post-SCT and a potential application for WT1 peptides in post-transplant immunotherapy of ALL. Figure Figure

scholarly journals The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation

2008 ◽  
Vol 82 (23) ◽  
pp. 11637-11650 ◽  
Author(s):  
Verena Böhm ◽  
Christian O. Simon ◽  
Jürgen Podlech ◽  
Christof K. Seckert ◽  
Dorothea Gendig ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Negative Feedback ◽  
Cd8 T Cells ◽  
Viral Gene Expression ◽  
Cd8 T Cell ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Infected Cells

ABSTRACT Cytomegaloviruses express glycoproteins that interfere with antigen presentation to CD8 T cells. Although the molecular modes of action of these “immunoevasins” differ between cytomegalovirus species, the convergent biological outcome is an inhibition of the recognition of infected cells. In murine cytomegalovirus, m152/gp40 retains peptide-loaded major histocompatibility complex class I molecules in a cis-Golgi compartment, m06/gp48 mediates their vesicular sorting for lysosomal degradation, and m04/gp34, although not an immunoevasin in its own right, appears to assist in the concerted action of all three molecules. Using the Ld-restricted IE1 epitope YPHFMPTNL in the BALB/c mouse model as a paradigm, we provide here an explanation for the paradox that immunoevasins enhance CD8 T-cell priming although they inhibit peptide presentation in infected cells. Adaptive immune responses are initiated in the regional lymph node (RLN) draining the site of pathogen exposure. In particular for antigens that are not virion components, the magnitude of viral gene expression providing the antigens is likely a critical parameter in priming efficacy. We have therefore focused on the events in the RLN and have related priming to intranodal viral gene expression. We show that immunoevasins enhance priming by downmodulating an early CD8 T-cell-mediated “negative feedback” control of the infection in the cortical region of the RLN, thus supporting the model that immunoevasins improve antigen supply for indirect priming by uninfected antigen-presenting cells. As an important consequence, these findings predict that deletion of immunoevasin genes in a replicative vaccine virus is not a favorable option but may, rather, be counterproductive.

Gene Expression Patterns Associated With Tumor-infiltrating CD4+  and CD8+ T Cells in Invasive Breast Carcinomas 

2020 ◽  
Author(s):  
Zhanwei Wang ◽  
Xi Yang ◽  
Jiamin Xu ◽  
Yuefen Pan ◽  
Junjun Shen ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Expression Patterns ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Gene Expression Patterns ◽  
Cerna Network ◽  
Immune Score

Abstract Objective: This study investigated the gene expression patterns associated with tumor-infiltrating CD4+ and CD8+ T cells in invasive breast carcinomas.Methods: The gene expression data and corresponding clinical phenotype data from the Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) were downloaded. The stromal and immune score were calculated using ESTIMATE. The differentially expressed genes (DEGs) with a high vs. low stromal score and a high vs. low immune score were screened and then functionally enriched. The tumor-infiltrating immune cells were investigated using the Cibersort algorithm, and the CD4+ and CD8+ T cell-related genes were identified using a Spearman correlation test of infiltrating abundance with the DEGs. Moreover, the miRNA-mRNA pairs and lncRNA-miRNA pairs were predicted to construct the competing endogenous RNAs (ceRNA) network. Kaplan-Meier (K-M) survival curves were also plotted.Results: In total, 478 DEGs with a high vs. low stromal score and 796 DEGs with a high vs. low immune score were identified. In addition, 39 CD4+ T cell-related genes and 78 CD8+ T cell-related genes were identified; of these, 14 genes were significantly associated with the prognosis of BRCA patients. Moreover, for CD4+ T cell-related genes, the chr22-38_28785274-29006793.1-–miR-34a/c-5p–CAPN6 axis was identified from the ceRNA network, whereas the chr22-38_28785274-29006793.1–miR-494-3p–SLC9A7 axis was identified for CD8+ T cell-related genes.Conclusions: The chr22-38_28785274-29006793.1-–miR-34a/c-5p–CAPN6 axis and the chr22-38_28785274-29006793.1–miR-494-3p–SLC9A7 axis might regulate cellular activities associated with CD4+ and CD8+ T cell infiltration, respectively, in BRCA.

scholarly journals Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8+ T-cell response

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3363-3370 ◽  
Author(s):  
Monchou Fann ◽  
Jason M. Godlove ◽  
Marta Catalfamo ◽  
William H. Wood ◽  
Francis J. Chrest ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Differential Gene Expression ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Memory Cd8 T Cells ◽  
Differential Gene ◽  
H3k9 Acetylation

Abstract To understand the molecular basis for the rapid and robust memory T-cell responses, we examined gene expression and chromatin modification by histone H3 lysine 9 (H3K9) acetylation in resting and activated human naive and memory CD8+ T cells. We found that, although overall gene expression patterns were similar, a number of genes are differentially expressed in either memory or naive cells in their resting and activated states. To further elucidate the basis for differential gene expression, we assessed the role of histone H3K9 acetylation in differential gene expression. Strikingly, higher H3K9 acetylation levels were detected in resting memory cells, prior to their activation, for those genes that were differentially expressed following activation, indicating that hyperacetylation of histone H3K9 may play a role in selective and rapid gene expression of memory CD8+ T cells. Consistent with this model, we showed that inducing high levels of H3K9 acetylation resulted in an increased expression in naive cells of those genes that are normally expressed differentially in memory cells. Together, these findings suggest that differential gene expression mediated at least in part by histone H3K9 hyperacetylation may be responsible for the rapid and robust memory CD8+ T-cell response.

scholarly journals Breast Tumor Microenvironment in Black Women: A Distinct Signature of CD8+ T Cell Exhaustion

2021 ◽  
Author(s):  
Song Yao ◽  
Ting-Yuan David Cheng ◽  
Ahmed Elkhanany ◽  
Li Yan ◽  
Angela Omilian ◽  
...  
Keyword(s):  
T Cells ◽  
Black Women ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Racial Differences ◽  
Cd8 T Cells ◽  
Tumor Biology ◽  
Cd8 T Cell ◽  
Health Study ◽  
Immune Phenotypes

Abstract Background Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment (TME), constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women. Methods Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast TME from 1,315 patients from the Women’s Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in three independent cohorts. Results We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence, but the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+/B cell response, and further, a more exhausted CD8+ T cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor (HR)-positive patients. Among HR-negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival. Conclusions Our findings of a distinct exhausted CD8+ T cell signature in Black breast cancer patients indicates an immunobiological basis for their more aggressive disease, and also a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.

scholarly journals Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection

2011 ◽  
Vol 209 (1) ◽  
pp. 77-91 ◽  
Author(s):  
Chao Wang ◽  
Ann J. McPherson ◽  
R. Brad Jones ◽  
Kim S. Kawamura ◽  
Gloria H.Y. Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chronic Infection ◽  
Chronic Phase ◽  
Cd8 T Cell ◽  
Dependent Manner ◽  
Viral Control ◽  
Potential Biomarker

The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL–deficient mice have defects in viral control early, but not late, in chronic infection. TGFβ induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels. A combination treatment with IL-7 and agonist anti–4-1BB antibody at 3 wk after LCMV clone 13 infection expands T cells and reduces viral load in a TRAF1-dependent manner. Moreover, transfer of TRAF1+ but not TRAF1− memory T cells at the chronic stage of infection reduces viral load. These findings identify TRAF1 as a potential biomarker of HIV-specific CD8 T cell fitness during the chronic phase of disease and a target for therapy.

scholarly journals Irradiation Suppresses IFNγ-Mediated PD-L1 and MCL1 Expression in EGFR-Positive Lung Cancer to Augment CD8+ T Cells Cytotoxicity

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2515
Author(s):  
Chun-I. Wang ◽  
Yi-Fang Chang ◽  
Zong-Lin Sie ◽  
Ai-Sheng Ho ◽  
Jung-Shan Chang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Irradiation Effect ◽  
Western Blots ◽  
Stat3 Phosphorylation

Tumor cells express immune checkpoints to exhaust CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical applications. However, the radiotherapy-mediated molecular mechanism affecting CD8+ T cell activity remains elusive. We aimed to uncover the mechanism of radiotherapy augmenting cytotoxic CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive NSCLC cell lines were co-cultured with CD8+ T cells from healthy volunteers. Tumor cell viability and apoptosis were consequently measured. IFNγ was identified secreted by CD8+ T cells and PBMCs. Therefore, RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. The irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and western blots. We found that the co-culture of tumor cells stimulated the increase of granzyme B and IFNγ in CD8+ T, but A549 exhibited resistance against CD8+ T cytotoxicity compared to HCC827. Irradiation inhibited A549 proliferation and enhanced apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. We found that IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1 (p < 0.05). In RNAseq analysis, MCL1 was identified and increased by the IFNγ-STAT3 axis (p < 0.05). We demonstrated that irradiation specifically inhibited phosphorylation on STAT1 and STAT3 in IFNγ-treated A549, resulting in reductions of PD-L1 and MCL1 (both p < 0.05). Moreover, knockdowns of STAT3 and MCL1 increased the PBMCs-mediated anti-A549 effect. This study demonstrated that A549 expressed MCL1 to resist CD8+ T cell-mediated tumor apoptosis. In addition, we found that irradiation suppressed IFNγ-mediated STAT3 phosphorylation and PD-L1 and MCL1 expression, revealing a potential mechanism of radiotherapy augmenting immune surveillance.

scholarly journals Single-cell analyses identify tobacco smoke exposure-associated, dysfunctional CD16+ CD8 T cells with high cytolytic potential in peripheral blood

2019 ◽  
Author(s):  
Suzanne N. Martos ◽  
Michelle R. Campbell ◽  
Oswaldo A. Lozoya ◽  
Brian D. Bennett ◽  
Isabel J.B. Thompson ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Tobacco Smoke ◽  
Peripheral Blood ◽  
Cd8 T Cell ◽  
Tobacco Smoke Exposure ◽  
Mass Cytometry

SUMMARYTobacco smoke exposure has been found to impact immune response, leukocyte subtypes, DNA methylation, and gene expression in human whole blood. Analysis with single cell technologies will resolve smoking associated (sub)population compositions, gene expression differences, and identification of rare subtypes masked by bulk fraction data. To characterize smoking-related gene expression changes in primary immune cells, we performed single-cell RNA sequencing (scRNAseq) on >45,000 human peripheral blood mononuclear cells (PBMCs) from smokers (n=4) and nonsmokers (n=4). Major cell type population frequencies showed strong correlation between scRNAseq and mass cytometry. Transcriptomes revealed an altered subpopulation of Natural Killer (NK)-like T lymphocytes in smokers, which expressed elevated levels of FCGR3A (gene encoding CD16) compared to other CD8 T cell subpopulations. Relatively rare in nonsmokers (median: 1.8%), the transcriptionally unique subset of CD8 T cells comprised 7.3% of PBMCs in smokers. Mass cytometry confirmed a significant increase (p = 0.03) in the frequency of CD16+ CD8 T cells in smokers. The majority of CD16+ CD8 T cells were CD45RA positive, indicating an effector memory re-expressing CD45RA T cell (TEMRA) phenotype. We expect that cigarette smoke alters CD8 T cell composition by shifting CD8 T cells toward differentiated functional states. Pseudotemporal ordering of CD8 T cell clusters revealed that smokers’ cells were biased toward later pseudotimes, and characterization of established markers in CD8 T cell subsets indicates a higher frequency of terminally differentiated cells in smokers than in nonsmokers, which corresponded with a lower frequency in naïve CD8 T cells. Consistent with an end-stage TEMRA phenotype, FCGR3A-expressing CD8 T cells were inferred as the most differentiated cluster by pseudotime analysis and expressed markers linked to senescence. Examination of differentially expressed genes in other PBMCs uncovered additional senescence-associated genes in CD4 T cells, NKT cells, NK cells, and monocytes. We also observed elevated Tregs, inducers of T cell senescence, in smokers. Taken together, our results suggest smoking-induced, senescence-associated immune cell dysregulation contributes to smoking-mediated pathologies.

scholarly journals Running to Stand Still: Naive CD8+ T Cells Actively Maintain a Program of Quiescence

2020 ◽  
Vol 21 (24) ◽  
pp. 9773
Author(s):  
Taylah J. Bennett ◽  
Vibha A. V. Udupa ◽  
Stephen J. Turner
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Large Scale ◽  
Regulation Of Gene Expression ◽  
Cd8 T Cell ◽  
Epigenetic Mechanisms ◽  
Crucial Difference ◽  
Cell Quiescence

CD8+ T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8+ T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and gene expression. Importantly, recent evidence demonstrates that the epigenetic mechanisms that regulate the capacity for rapid effector function of memory T cells are shared by innate immune cells such as natural killer (NK) cells. Thus, it appears that the crucial difference between innate and adaptive immunity is the presence of the naïve state. This important distinction raises an intriguing new hypothesis, that the naïve state was evolutionary installed to restrain a default program of effector and memory differentiation in response to antigen recognition. We argue that the hallmark of adaptive T immunity is therefore the naïve program, which actively maintains CD8+ T cell quiescence until receipt of appropriate activation signals. In this review, we examine the mechanistic control of naïve CD8+ T cell quiescence and summarise the multiple levels of restraint imposed in naïve cells in to limit spontaneous and inappropriate activation. This includes epigenetic mechanisms and transcription factor (TF) regulation of gene expression, in addition to novel inhibitory receptors, abundance of RNA, and protein degradation.

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

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