Quantitative Characterization of Immune Cells by Measuring Cellular Signal Transduction Pathway Activity

Overview

Journal Sci Rep

Specialty Science

Date 2024 Oct 18

PMID 39424625

Authors

Wilbert Bouwman

Wim Verhaegh

Arie van Doorn

Reinier Raymakers

Tom van der Poll

Anja van de Stolpe

Affiliations

Soon will be listed here.

Abstract

For many diseases, including cancer, infections, and auto-immune diseases, the immune response is a major determinant of disease progression, response to therapy, and clinical outcome. Innate and adaptive immune responses are controlled by coordinated activity of different immune cell types. The functional activity state of immune cells is determined by Signal Transduction Pathways (STPs). A recently developed technology (Simultaneous Transcriptome-based Activity Profiling of Signal Transduction Pathways, STAP-STP) enables simultaneous and quantitative activity measurement of relevant STPs in immune cells based on mRNA-analysis. STAP-STP technology was used to analyze public transcriptome data of a variety of immune cell types in resting and activated functional state. In addition, a clinical study on rheumatoid arthritis (RA) was analyzed to illustrate utility of the technology. Per sample, activity of androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, NFκB, JAK-STAT1/2, and JAK-STAT3 STPs was calculated, generating an STP activity profile (SAP) consisting of 9 activity scores. Each analyzed immune cell type, i.e. naive/resting and immune-activated CD4 + and CD8 + T cells, T helper cells, B cells, NK cells, monocytes, macrophages, and dendritic cells, had a reproducible and characteristic SAP, reflecting both cell type and its activity state. Analysis of clinical RA samples revealed increased TGFβ STP activity in whole blood samples. In conclusion, STAP-STP technology enables quantitative measurement of the functional activity state of immune cells of the innate and adaptive immune system. Aside from diagnostic applications, utility lies in unravelling abnormal immune function in disease and immunomodulatory drug development.

Citing Articles

Comparison Between Signal Transduction Pathway Activity in Blood Cells of Sepsis Patients and Laboratory Models.

Bouwman W, Raymakers R, van der Poll T, van de Stolpe A Cells. 2025; 14(4).

PMID: 39996782 PMC: 11854017. DOI: 10.3390/cells14040311.

References

Lai J, Lai K, Zeng W, Chuang K, Altuwaijri S, Chang C . Androgen receptor influences on body defense system via modulation of innate and adaptive immune systems: lessons from conditional AR knockout mice. Am J Pathol. 2012; 181(5):1504-12. PMC: 3483803. DOI: 10.1016/j.ajpath.2012.07.008. View

Futosi K, Fodor S, Mocsai A . Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol. 2013; 17(3):638-50. PMC: 3827506. DOI: 10.1016/j.intimp.2013.06.034. View

Stegmann K, Bjorkstrom N, Veber H, Ciesek S, Riese P, Wiegand J . Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology. 2010; 138(5):1885-97. DOI: 10.1053/j.gastro.2010.01.051. View

Li M, Wan Y, Flavell R . T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity. 2007; 26(5):579-91. DOI: 10.1016/j.immuni.2007.03.014. View

Luo K . Signaling Cross Talk between TGF-β/Smad and Other Signaling Pathways. Cold Spring Harb Perspect Biol. 2016; 9(1). PMC: 5204325. DOI: 10.1101/cshperspect.a022137. View

Barber G . STING: infection, inflammation and cancer. Nat Rev Immunol. 2015; 15(12):760-70. PMC: 5004891. DOI: 10.1038/nri3921. View

Du X, Tang Y, Xu H, Lit L, Walker W, Ashwood P . Genomic profiles for human peripheral blood T cells, B cells, natural killer cells, monocytes, and polymorphonuclear cells: comparisons to ischemic stroke, migraine, and Tourette syndrome. Genomics. 2006; 87(6):693-703. DOI: 10.1016/j.ygeno.2006.02.003. View

Walter G, Fleskens V, Frederiksen K, Rajasekhar M, Menon B, Gerwien J . Phenotypic, Functional, and Gene Expression Profiling of Peripheral CD45RA+ and CD45RO+ CD4+CD25+CD127(low) Treg Cells in Patients With Chronic Rheumatoid Arthritis. Arthritis Rheumatol. 2015; 68(1):103-16. PMC: 4832388. DOI: 10.1002/art.39408. View

Kotz K, Xiao W, Miller-Graziano C, Qian W, Russom A, Warner E . Clinical microfluidics for neutrophil genomics and proteomics. Nat Med. 2010; 16(9):1042-7. PMC: 3136804. DOI: 10.1038/nm.2205. View

10.

Zaslavsky E, Hershberg U, Seto J, Pham A, Marquez S, Duke J . Antiviral response dictated by choreographed cascade of transcription factors. J Immunol. 2010; 184(6):2908-17. PMC: 2856074. DOI: 10.4049/jimmunol.0903453. View

11.

Chen W, Ten Dijke P . Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol. 2016; 16(12):723-740. DOI: 10.1038/nri.2016.112. View

12.

Amrhein V, Greenland S, McShane B . Scientists rise up against statistical significance. Nature. 2019; 567(7748):305-307. DOI: 10.1038/d41586-019-00857-9. View

13.

Allantaz F, Cheng D, Bergauer T, Ravindran P, Rossier M, Ebeling M . Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression. PLoS One. 2012; 7(1):e29979. PMC: 3262799. DOI: 10.1371/journal.pone.0029979. View

14.

Reyes M, Filbin M, Bhattacharyya R, Billman K, Eisenhaure T, Hung D . An immune-cell signature of bacterial sepsis. Nat Med. 2020; 26(3):333-340. PMC: 7235950. DOI: 10.1038/s41591-020-0752-4. View

15.

Vallat L, Kemper C, Jung N, Maumy-Bertrand M, Bertrand F, Meyer N . Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2012; 110(2):459-64. PMC: 3545767. DOI: 10.1073/pnas.1211130110. View

16.

Oh H, Ghosh S . NF-κB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev. 2013; 252(1):41-51. PMC: 3576882. DOI: 10.1111/imr.12033. View

17.

Tasaki S, Suzuki K, Kassai Y, Takeshita M, Murota A, Kondo Y . Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission. Nat Commun. 2018; 9(1):2755. PMC: 6048065. DOI: 10.1038/s41467-018-05044-4. View

18.

Cante-Barrett K, Holtzer L, van Ooijen H, Hagelaar R, Cordo V, Verhaegh W . A Molecular Test for Quantifying Functional Notch Signaling Pathway Activity in Human Cancer. Cancers (Basel). 2020; 12(11). PMC: 7692325. DOI: 10.3390/cancers12113142. View

19.

Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y . Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020; 146(1):110-118. PMC: 7152876. DOI: 10.1016/j.jaci.2020.04.006. View

20.

Gautier L, Cope L, Bolstad B, Irizarry R . affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004; 20(3):307-15. DOI: 10.1093/bioinformatics/btg405. View