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Cyclophilin A associates with and regulates the activity of ZAP70 in TCR/CD3-stimulated T cells

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Abstract

The ZAP70 protein tyrosine kinase (PTK) couples stimulated T cell antigen receptors (TCRs) to their downstream signal transduction pathways and is sine qua non for T cell activation and differentiation. TCR engagement leads to activation-induced post-translational modifications of ZAP70, predominantly by kinases, which modulate its conformation, leading to activation of its catalytic domain. Here, we demonstrate that ZAP70 in TCR/CD3-activated mouse spleen and thymus cells, as well as human Jurkat T cells, is regulated by the peptidyl-prolyl cis–trans isomerase (PPIase), cyclophilin A (CypA) and that this regulation is abrogated by cyclosporin A (CsA), a CypA inhibitor. We found that TCR crosslinking promoted a rapid and transient, Lck-dependent association of CypA with the interdomain B region, at the ZAP70 regulatory domain. CsA inhibited CypA binding to ZAP70 and prevented the colocalization of CypA and ZAP70 at the cell membrane. In addition, imaging analyses of antigen-specific T cells stimulated by MHC-restricted antigen-fed antigen-presenting cells revealed the recruitment of ZAP70-bound CypA to the immunological synapse. Enzymatically active CypA downregulated the catalytic activity of ZAP70 in vitro, an effect that was reversed by CsA in TCR/CD3-activated normal T cells but not in CypA-deficient T cells, and further confirmed in vivo by FRET-based studies. We suggest that CypA plays a role in determining the activity of ZAP70 in TCR-engaged T cells and impact on T cell activation by intervening with the activity of multiple downstream effector molecules.

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Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

Abbreviations

C3G:

CrkII binding of guanine-nucleotide releasing factor

c-Cbl:

Casitas B-lineage lymphoma

cfb3:

Cytoplasmic fragment of human erythrocyte band 3

CrkII:

CT10 regulator of kinase II

CypA:

Cyclophilin A

CsA:

Cyclosporin A

FRET:

Fluorescence resonance energy transfer

HRP:

Horseradish peroxidase

IP3 :

Inositol trisphosphate

IS:

Immunological synapse

ITAM:

Immunoreceptor tyrosine-based activation motifs

Itk:

Interleukin-2-inducible T cell kinase

JNK:

Jun N-terminal kinase

LAT:

Linker of activated T cells

Lck:

Lymphocyte-specific protein tyrosine kinase

MAPK:

Mitogen-activated protein kinase

NFAT:

Nuclear factor of activated T cells

Pin1:

Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1

PKCα:

Protein kinase C α

PLC:

Phospholipase C

PPIase:

Peptidyl-prolyl cis–trans isomerases

SCID:

Severe combined immunodeficiency

Sts1:

Suppressor of TCR signaling 1

TCR:

T cell antigen receptor

WCL:

Whole-cell lysates

ZAP70:

ζ-Chain-associated protein of 70 kDa

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Acknowledgements

We thank Ms. Margalit Krup for technical assistance, Ms. Caroline Simon, and Ms. Judith Isakov for editorial assistance, and Drs. Joseph B. Bolen, Michael Emerman, Annemarie Lellouch, and Tony Pawson, for their gifts of reagents. The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: Jurkat T-Cells CypA -/-, ARP-10095, contributed by Drs. D. Braaten and J. Luban.

Funding

This work was funded in part by the Israel Science Foundation Grants No. 1235/17 (NI) and 2368/19 (EL), the USA-Israel Binational Science Foundation Grant No. 2013034 (NI), the Jacki and Bruce Barron Cancer Research Scholars’ Program, a partnership between the Israel Cancer Research Fund (ICRF) and the City of Hope (Grant No. 87735611 (NI)), postdoctoral fellowships provided by the Planning and Budgeting Committee (PBC) of the Israel Council for Higher Education (AKA and PRN) and doctoral fellowships provided by the Kreitman School of Advanced Graduate Studies, Ben-Gurion University of the Negev (NPA).

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  1. Awadhesh Kumar Arya

    Present address: Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

  2. Pulak Ranjan Nath

    Present address: Clinical and Translational Immunology Unit, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892-1857, USA

  3. Nikhil Ponnoor Anto and Awadhesh Kumar Arya equally contributed to this work.

Authors and Affiliations

  1. The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, 84105, Beer Sheva, Israel

    Nikhil Ponnoor Anto, Awadhesh Kumar Arya, Amitha Muraleedharan, Jakeer Shaik, Pulak Ranjan Nath, Etta Livneh, Alex Braiman & Noah Isakov

  2. Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

    Zuoming Sun

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Contributions

NI conceived the study, designed experiments, and supervised the project; NPA, AKA, AM, JS, and PRN carried out the experiments; ZS, AB, and NI analyzed the data; EL provided essential tools for the study; NPA, AKA, and NI wrote the manuscript. All authors commented on the previous versions of the manuscript. All authors have read and approved the final manuscript and have given consent for publishing the work.

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Correspondence to Noah Isakov.

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This study was approved in advance by the Ben-Gurion University Institutional Animal Care and Use Committee and conducted in accordance with the Israeli Animal Welfare Act following the guidelines of the Guide for Care and Use of Laboratory Animals (National Research Council 1996). The Animal ethical clearance protocol used for this research is IL-44–08-2017.

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Anto, N.P., Arya, A.K., Muraleedharan, A. et al. Cyclophilin A associates with and regulates the activity of ZAP70 in TCR/CD3-stimulated T cells. Cell. Mol. Life Sci. 80, 7 (2023). https://doi.org/10.1007/s00018-022-04657-9

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