Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail. PATIENTS AND METHODS Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. RESULTS At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors. CONCLUSION We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.

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Borna disease, a progressive meningoencephalomyelitis as a model for CD4+ T cell-mediated immunopathology in the brain.

Journal of Experimental Medicine ◽

10.1084/jem.170.3.1045 ◽

1989 ◽

Vol 170 (3) ◽

pp. 1045-1050 ◽

Cited By ~ 46

Author(s):

J A Richt ◽

L Stitz ◽

H Wekerle ◽

R Rott

Keyword(s):

T Cells ◽

T Cell ◽

Cell Line ◽

Mhc Class Ii ◽

Adoptive Transfer ◽

Cd4 T Cells ◽

Immune Cell ◽

Cd4 T Cell ◽

The Brain ◽

Borna Disease

A homogeneous T cell line NM1 with Borna disease (BD) virus reactivity could be established. The NM1 cells have been characterized as CD4+ T cells. Adoptive transfer revealed that this MHC class II-restricted immune cell is responsible for the immunopathological effect leading to BD, a progressive meningoencephalomyelitis.

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CD4+ T-cell dynamics in primary cytomegalovirus infection

Transplantation Proceedings ◽

10.1016/s0041-1345(01)02004-8 ◽

2001 ◽

Vol 33 (3) ◽

pp. 2313-2314 ◽

Cited By ~ 5

Author(s):

R.J Rentenaar ◽

L.E Gamadia ◽

N van der Hoek ◽

F.N.J van Diepen ◽

R Boom ◽

...

Keyword(s):

T Cell ◽

Cytomegalovirus Infection ◽

Cd4 T Cell ◽

Cell Dynamics ◽

Primary Cytomegalovirus Infection

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Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection

Journal of Clinical Investigation ◽

10.1172/jci131696 ◽

2019 ◽

Vol 130 (1) ◽

pp. 523-538 ◽

Cited By ~ 4

Author(s):

Aleks Guvenel ◽

Agnieszka Jozwik ◽

Stephanie Ascough ◽

Seng Kuong Ung ◽

Suzanna Paterson ◽

...

Keyword(s):

T Cell ◽

Cd4 T Cell ◽

Cell Dynamics ◽

Rsv Infection

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Comprehensive Analysis of Cell Population Dynamics and Related Core Genes During Vitiligo Development

Frontiers in Genetics ◽

10.3389/fgene.2021.627092 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jingzhan Zhang ◽

Shirong Yu ◽

Wen Hu ◽

Man Wang ◽

Dilinuer Abudoureyimu ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Immune Cell ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Healthy Controls ◽

Cell Abundance

Vitiligo is a common immune-related depigmentation condition, and its pathogenesis remains unclear. This study used a combination of bioinformatics methods and expression analysis techniques to explore the relationship between immune cell infiltration and gene expression in vitiligo. Previously reported gene expression microarray data from the skin (GSE53146 and GSE75819) and peripheral blood (GSE80009 and GSE90880) of vitiligo patients and healthy controls was used in the analysis. R software was used to filter the differentially expressed genes (DEGs) in each dataset, and the KOBAS 2.0 server was used to perform functional enrichment analysis. Compared with healthy controls, the upregulated genes in skin lesions and peripheral blood leukocytes of vitiligo patents were highly enriched in immune response pathways and inflammatory response signaling pathways. Immunedeconv software and the EPIC method were used to analyze the expression levels of marker genes to obtain the immune cell population in the samples. In the lesional skin of vitiligo patients, the proportions of macrophages, B cells and NK cells were increased compared with healthy controls. In the peripheral blood of vitiligo patients, CD8+ T cells and macrophages were significantly increased. A coexpression analysis of the cell populations and DEGs showed that differentially expressed immune and inflammation response genes had a strong positive correlation with macrophages. The TLR4 receptor pathway, interferon gamma-mediated signaling pathway and lipopolysaccharide-related pathway were positively correlated with CD4+ T cells. Regarding immune response-related genes, the overexpression of IFITM2, TNFSF10, GZMA, ADAMDEC1, NCF2, ADAR, SIGLEC16, and WIPF2 were related to macrophage abundance, while the overexpression of ICOS, GPR183, RGS1, ILF2 and CD28 were related to CD4+ T cell abundance. GZMA and CXCL10 expression were associated with CD8+ T cell abundance. Regarding inflammatory response-related genes, the overexpression of CEBPB, ADAM8, CXCR3, and TNIP3 promoted macrophage infiltration. Only ADORA1 expression was associated with CD4+ T cell infiltration. ADAM8 and CXCL10 expression were associated with CD8+ T cell abundance. The overexpression of CCL18, CXCL10, FOS, NLRC4, LY96, HCK, MYD88, and KLRG1, which are related to inflammation and immune responses, were associated with macrophage abundance. We also found that immune cells infiltration in vitiligo was associated with antigen presentation-related genes expression. The genes and pathways identified in this study may point to new directions for vitiligo treatment.

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Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

Infection and Immunity ◽

10.1128/iai.00193-17 ◽

2017 ◽

Vol 85 (10) ◽

Cited By ~ 1

Author(s):

Nicole V. Acuff ◽

Xin Li ◽

Krishna Latha ◽

Tamas Nagy ◽

Wendy T. Watford

Keyword(s):

T Cells ◽

T Cell ◽

Cell Function ◽

Immune Cell ◽

Cd4 T Cell ◽

Citrobacter Rodentium ◽

Wild Type ◽

Content Type ◽

Cell Recruitment ◽

Ifn Γ

ABSTRACT Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-γ), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 −/− mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 −/− mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-γ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag −/− mice, Tpl2 −/− CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 −/− mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function.

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