Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses

• Published in: Journal of autoimmunity 2018-11, Vol.94, p.45-55
• Main Authors: Sanchez-Blanco, Cristina, Clarke, Fiona, Cornish, Georgina H., Depoil, David, Thompson, Stephen J., Dai, Xuezhi, Rawlings, David J., Dustin, Michael L., Zamoyska, Rose, Cope, Andrew P., Purvis, Harriet A.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Autoimmunity; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; CD28 Antigens - antagonists & inhibitors; CD28 Antigens - genetics; CD28 Antigens - immunology; CD3 Complex - antagonists & inhibitors; CD3 Complex - genetics; CD3 Complex - immunology; Cell Proliferation - drug effects; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - pathology; Gene Expression Regulation; IFNγ; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - immunology; LFA-1; Lipid Bilayers - chemistry; Lipid Bilayers - immunology; Lipopolysaccharides - pharmacology; Lymphocyte Function-Associated Antigen-1 - genetics; Lymphocyte Function-Associated Antigen-1 - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin - pharmacology; Peptide Fragments - pharmacology; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - immunology; PTPN22; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; T-cell activation; Th1 Cells - drug effects; Th1 Cells - immunology; Th1 Cells - pathology
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2018.07.008

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response. •PTPN22R620W is one of the strongest risk factors for multiple autoimmune diseases.•In Ptpn22−/− and Ptpn22R619W mice IFNy+ Th1 cells preferentially and significantly expand with age or following immune challenge.•PTPN22 negatively regulates IFNγ+ Th1 cells by T-cell and dendritic cell LFA-1-ICAM-1 dependent mechanisms.•PTPN22 negatively regulates LFA-1 induced Th1 cells enhancing T-cell LFA-1 clustering and immune synapse formation.•Repeated stimulation of T-cells with Ptpn22−/− BMDC enhances Th1 responses.