. 2014 Aug; 15(9):790-7.
doi: 10.1038/ni.2959.

Integrative biology of T cell activation

Bernard Malissen 1 Claude Grégoire 2 Marie Malissen 1 Romain Roncagalli 2 
  • PMID: 25137453
  •     103 References
  •     48 citations


The activation of T cells mediated by the T cell antigen receptor (TCR) requires the interaction of dozens of proteins, and its malfunction has pathological consequences. Our major focus is on new developments in the systems-level understanding of the TCR signal-transduction network. To make sense of the formidable complexity of this network, we argue that 'fine-grained' methods are needed to assess the relationships among a few components that interact on a nanometric scale, and those should be integrated with high-throughput '-omic' approaches that simultaneously capture large numbers of parameters. We illustrate the utility of this integrative approach with the transmembrane signaling protein Lat, which is a key signaling hub of the TCR signal-transduction network, as a connecting thread.

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TCR and IL-7 Signaling Are Altered in the Absence of Functional GTPase of the Immune Associated Nucleotide Binding Protein 5 (GIMAP5).
Xi-Lin Chen, Daniel Serrano, +4 authors, Sheela Ramanathan.
PLoS One, 2016 Mar 31; 11(3). PMID: 27023180    Free PMC article.
Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217.
Elitza Ivanova, Nick Carpino.
Mol Immunol, 2016 Apr 01; 73. PMID: 27032069    Free PMC article.
Concerning immune synapses: a spatiotemporal timeline.
Alvaro Ortega-Carrion, Miguel Vicente-Manzanares.
F1000Res, 2016 Apr 20; 5. PMID: 27092248    Free PMC article.
Dual targeting of the thioredoxin and glutathione systems in cancer and HIV.
Moran Benhar, Iart Luca Shytaj, Jonathan S Stamler, Andrea Savarino.
J Clin Invest, 2016 May 03; 126(5). PMID: 27135880    Free PMC article.
Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms.
Olga Tsave, Savvas Petanidis, +5 authors, Athanasios Salifoglou.
Oxid Med Cell Longev, 2016 May 18; 2016. PMID: 27190573    Free PMC article.
Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol.
Feng Wang, Katharina Beck-García, +2 authors, Mark M Davis.
Nat Immunol, 2016 May 24; 17(7). PMID: 27213689    Free PMC article.
Protein tyrosine phosphatase SHP-1: resurgence as new drug target for human autoimmune disorders.
Yadhu Sharma, Samina Bashir, +2 authors, Farah Khan.
Immunol Res, 2016 May 25; 64(4). PMID: 27216862
Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT.
Baerbel Keller, Irina Zaidman, +11 authors, Polina Stepensky.
J Exp Med, 2016 Jun 01; 213(7). PMID: 27242165    Free PMC article.
What Happens in the Thymus Does Not Stay in the Thymus: How T Cells Recycle the CD4+-CD8+ Lineage Commitment Transcriptional Circuitry To Control Their Function.
Melanie S Vacchio, Rémy Bosselut.
J Immunol, 2016 Jun 05; 196(12). PMID: 27260768    Free PMC article.
Time-Course Study of the Transcriptome of Peripheral Blood Mononuclear Cells (PBMCs) from Sheep Infected with Fasciola hepatica.
Cristian A Alvarez Rojas, Jean-Pierre Scheerlinck, +3 authors, Aaron R Jex.
PLoS One, 2016 Jul 22; 11(7). PMID: 27438474    Free PMC article.
New Insights into How Trafficking Regulates T Cell Receptor Signaling.
Jieqiong Lou, Jérémie Rossy, +2 authors, Katharina Gaus.
Front Cell Dev Biol, 2016 Aug 11; 4. PMID: 27508206    Free PMC article.
The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.
Romain Roncagalli, Margot Cucchetti, +14 authors, Bernard Malissen.
J Exp Med, 2016 Nov 05; 213(11). PMID: 27647348    Free PMC article.
GTPase of the Immune-Associated Nucleotide Protein 5 Regulates the Lysosomal Calcium Compartment in T Lymphocytes.
Daniel Serrano, Farnaz Ghobadi, +3 authors, Sheela Ramanathan.
Front Immunol, 2017 Feb 23; 8. PMID: 28223986    Free PMC article.
Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors.
Jingjing Liang, Jun Lyu, +10 authors, Linrong Lu.
Nat Commun, 2017 Jun 10; 8. PMID: 28598420    Free PMC article.
Proteomics and Network Analyses Reveal Inhibition of Akt-mTOR Signaling in CD4+ T Cells by Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan.
Ahmad F Karim, Obondo J Sande, +8 authors, W Henry Boom.
Proteomics, 2017 Oct 11; 17(22). PMID: 28994205    Free PMC article.
SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma.
Grit Mutzbauer, Katja Maurus, +5 authors, Eva Geissinger.
Mod Pathol, 2017 Oct 21; 31(3). PMID: 29052597
Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy.
Sohini Roy, Arup K Bag, +3 authors, Kaustubh Datta.
Front Immunol, 2017 Oct 27; 8. PMID: 29067024    Free PMC article.
T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.
Sarah E Josefsson, Kanutte Huse, +10 authors, June H Myklebust.
Clin Cancer Res, 2017 Dec 09; 24(4). PMID: 29217528    Free PMC article.
P21-activated kinase 2 is essential in maintenance of peripheral Foxp3+ regulatory T cells.
Jinyong Choi, David Randall Pease, +2 authors, Hyewon Phee.
Immunology, 2018 Jan 04; 154(2). PMID: 29297928    Free PMC article.
New Chimeric Antigen Receptor Design for Solid Tumors.
Yuedi Wang, Feifei Luo, +2 authors, Yiwei Chu.
Front Immunol, 2018 Jan 10; 8. PMID: 29312360    Free PMC article.
Tolerance through Education: How Tolerogenic Dendritic Cells Shape Immunity.
Matthias P Domogalla, Patricia V Rostan, Verena K Raker, Kerstin Steinbrink.
Front Immunol, 2018 Jan 30; 8. PMID: 29375543    Free PMC article.
Highly Cited. Review.
CD8+ T Cells and NK Cells: Parallel and Complementary Soldiers of Immunotherapy.
Jillian Rosenberg, Jun Huang.
Curr Opin Chem Eng, 2018 Apr 07; 19. PMID: 29623254    Free PMC article.
Interference with KCTD9 inhibits NK cell activation and ameliorates fulminant liver failure in mice.
Xiaoping Zhang, Lin Zhu, +8 authors, Qin Ning.
BMC Immunol, 2018 Jun 27; 19(1). PMID: 29940856    Free PMC article.
New Paradigms in Cell Therapy: Repeated Dosing, Intravenous Delivery, Immunomodulatory Actions, and New Cell Types.
Marcin Wysoczynski, Abdur Khan, Roberto Bolli.
Circ Res, 2018 Jul 07; 123(2). PMID: 29976684    Free PMC article.
Functional TCR T cell screening using single-cell droplet microfluidics.
Aude I Segaliny, Guideng Li, +6 authors, Weian Zhao.
Lab Chip, 2018 Nov 07; 18(24). PMID: 30397689    Free PMC article.
Opportunities and Challenges for Antibodies against Intracellular Antigens.
Xiaofeng Yang, Shenxia Xie, +8 authors, Xiaoling Lu.
Theranostics, 2019 Nov 07; 9(25). PMID: 31695801    Free PMC article.
mDia1/3-dependent actin polymerization spatiotemporally controls LAT phosphorylation by Zap70 at the immune synapse.
D Thumkeo, Y Katsura, +9 authors, S Narumiya.
Sci Adv, 2020 Jan 09; 6(1). PMID: 31911947    Free PMC article.
Toll-like receptor chaperone HSP90B1 and the immune response to Mycobacteria.
Andrew D Graustein, Elizabeth A Misch, +11 authors, Thomas R Hawn.
PLoS One, 2018 Dec 15; 13(12). PMID: 30550567    Free PMC article.
Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response.
Patrick A Baeuerle, Jian Ding, +18 authors, Robert Hofmeister.
Nat Commun, 2019 May 09; 10(1). PMID: 31064990    Free PMC article.
T Cell Receptor (TCR)-Induced PLC-γ1 Sumoylation via PIASxβ and PIAS3 SUMO E3 Ligases Regulates the Microcluster Assembly and Physiological Function of PLC-γ1.
Qi-Long Wang, Jia-Qi Liang, +4 authors, Yingqiu Li.
Front Immunol, 2019 Mar 16; 10. PMID: 30873169    Free PMC article.
Harnessing regulatory T cell neuroprotective activities for treatment of neurodegenerative disorders.
Jatin Machhi, Bhavesh D Kevadiya, +4 authors, Howard E Gendelman.
Mol Neurodegener, 2020 Jun 07; 15(1). PMID: 32503641    Free PMC article.
Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation.
Jesse E Jun, Kayla R Kulhanek, +2 authors, Jeroen P Roose.
Sci Signal, 2019 Jul 25; 12(591). PMID: 31337738    Free PMC article.
Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance.
Weitao Que, Wen-Zhi Guo, Xiao-Kang Li.
Front Immunol, 2020 Nov 10; 11. PMID: 33162996    Free PMC article.
The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation.
Daiki Mori, Claude Grégoire, +12 authors, Bernard Malissen.
J Exp Med, 2020 Oct 31; 218(2). PMID: 33125054    Free PMC article.
Naturally Occurring Genetic Alterations in Proximal TCR Signaling and Implications for Cancer Immunotherapy.
Andrew Kent, Natalie V Longino, Allison Christians, Eduardo Davila.
Front Immunol, 2021 May 21; 12. PMID: 34012443    Free PMC article.
The GIMAP Family Proteins: An Incomplete Puzzle.
Marc-André Limoges, Maryse Cloutier, +2 authors, Sheela Ramanathan.
Front Immunol, 2021 Jun 18; 12. PMID: 34135906    Free PMC article.
Vanadium in Biosphere and Its Role in Biological Processes.
Deepika Tripathi, Veena Mani, Ravi Prakash Pal.
Biol Trace Elem Res, 2018 Mar 11; 186(1). PMID: 29524196
The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity.
Yael Dinur-Schejter, Irina Zaidman, Hagar Mor-Shaked, Polina Stepensky.
Front Immunol, 2021 Aug 31; 12. PMID: 34456914    Free PMC article.
T cells at work: How post-transcriptional mechanisms control T cell homeostasis and activation.
Anouk P Jurgens, Branka Popović, Monika C Wolkers.
Eur J Immunol, 2021 Jun 29; 51(9). PMID: 34180545    Free PMC article.
Systems-level conservation of the proximal TCR signaling network of mice and humans.
Philippe Nicolas, Jocelyn Ollier, +12 authors, Bernard Malissen.
J Exp Med, 2022 Jan 22; 219(2). PMID: 35061003    Free PMC article.
Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity.
Chie Sugimoto, Yukie Murakami, +2 authors, Hiroshi Wakao.
Elife, 2022 Apr 06; 11. PMID: 35379387    Free PMC article.