CD28 Superagonist Shock and Blockage of Motogenic T Cell Cascade

T cell motility is arrested by T cell receptor (TCR) recognition of cognate peptide-MHC (pMHC) complexes on antigen-presenting cells (1). Co-stimulation through CD28 is required for immune responses but its influence on T cell motility is less clear than that of the TCR. Ligation of CD28 and TCR collaborate to block a distinct protease-controlled step in the motogenic T cell cascade directed by the large transmembrane receptor low density lipoprotein receptor-related protein 1 (LRP1) and its high molecular weight ligand thrombospondin-1 (TSP-1) (2–9). Here I describe how blockage of this protease step is a likely explanation for the instantaneous arrest and cytokine storm elicited by the CD28 superagonist TGN1412 in a clinical trial in 2006 (10), which illustrates the power of the LRP1-targeted protease-dependent T cell control.

[1]  K. Sundqvist.  T Cell Motility─How Is It Regulated? , 2020, Frontiers in Immunology.

[2]  P. Bongrand,et al.  TCR–pMHC kinetics under force in a cell-free system show no intrinsic catch bond, but a minimal encounter duration before binding , 2019, Proceedings of the National Academy of Sciences.

[3]  M. Suto,et al.  Thrombospondin-1 regulation of latent TGF-β activation: A therapeutic target for fibrotic disease. , 2017, Matrix biology : journal of the International Society for Matrix Biology.

[4]  K. Sundqvist,et al.  T‐cell regulation through a basic suppressive mechanism targeting low‐density lipoprotein receptor‐related protein 1 , 2017, Immunology.

[5]  Jae-Ho Cho,et al.  T Cell's Sense of Self: a Role of Self-Recognition in Shaping Functional Competence of Naïve T Cells , 2017, Immune network.

[6]  C. Boudier,et al.  Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation* , 2016, The Journal of Biological Chemistry.

[7]  G. Bu,et al.  Neuronal LRP1 Regulates Glucose Metabolism and Insulin Signaling in the Brain , 2015, The Journal of Neuroscience.

[8]  M. Uzunel,et al.  Antigen‐induced regulation of T‐cell motility, interaction with antigen‐presenting cells and activation through endogenous thrombospondin‐1 and its receptors , 2015, Immunology.

[9]  K. Sundqvist,et al.  Regulation of T‐lymphocyte motility, adhesion and de‐adhesion by a cell surface mechanism directed by low density lipoprotein receptor‐related protein 1 and endogenous thrombospondin‐1 , 2014, Immunology.

[10]  J. Castle,et al.  Cell Contact–Dependent Priming and Fc Interaction with CD32+ Immune Cells Contribute to the TGN1412-Triggered Cytokine Response , 2014, The Journal of Immunology.

[11]  K. Sundqvist,et al.  A cytokine‐controlled mechanism for integrated regulation of T‐lymphocyte motility, adhesion and activation , 2013, Immunology.

[12]  Ming O. Li,et al.  TGF-β: Guardian of T Cell Function , 2013, The Journal of Immunology.

[13]  Hermann Einsele,et al.  Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412. , 2011, Blood.

[14]  A. Huttenlocher,et al.  A Live Imaging Cell Motility Screen Identifies Prostaglandin E2 as a T Cell Stop Signal Antagonist , 2011, The Journal of Immunology.

[15]  Mark M. Davis,et al.  CD4+ T-cell synapses involve multiple distinct stages , 2011, Proceedings of the National Academy of Sciences.

[16]  L Findlay,et al.  Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T‐cells , 2010, British journal of pharmacology.

[17]  I. De Meester,et al.  A CD26-Controlled Cell Surface Cascade for Regulation of T Cell Motility and Chemokine Signals1 , 2009, The Journal of Immunology.

[18]  D. Strickland,et al.  LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. , 2008, Physiological reviews.

[19]  J. Rathmell,et al.  Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways1 , 2008, The Journal of Immunology.

[20]  A. Flügel,et al.  A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats. , 2008, The Journal of clinical investigation.

[21]  A. Chakraborty,et al.  T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation , 2008, Nature Immunology.

[22]  A. Jaramillo,et al.  Enhanced Allograft Survival and Modulation of T‐Cell Alloreactivity Induced by Inhibition of MMP/ADAM Enzymatic Activity , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  Richard G. W. Anderson,et al.  LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDGF Signals in the Vascular Wall: Implications for Marfan Syndrome , 2007, PloS one.

[24]  Mark J. Miller,et al.  MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo , 2007, Proceedings of the National Academy of Sciences.

[25]  Shu Shun Li,et al.  Endogenous thrombospondin-1 is a cell-surface ligand for regulation of integrin-dependent T-lymphocyte adhesion. , 2006, Blood.

[26]  Nicki Panoskaltsis,et al.  Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. , 2006, The New England journal of medicine.

[27]  Margaret Clotworthy,et al.  On the effects of cycloheximide on cell motility and polarisation in Dictyostelium discoideum , 2006, BMC cell biology.

[28]  T. Hünig,et al.  CD28 superagonists: mode of action and therapeutic potential. , 2005, Immunology letters.

[29]  Shu Shun Li,et al.  Autocrine Regulation of T Cell Motility by Calreticulin-Thrombospondin-1 Interaction1 , 2005, The Journal of Immunology.

[30]  F. Tang,et al.  Cellular growth inhibition by IGFBP‐3 and TGF‐β1 requires LRP‐1 , 2003 .

[31]  R. Germain,et al.  Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes , 2002, Nature.

[32]  P. Bornstein,et al.  The Low Density Lipoprotein Receptor-related Protein Modulates Levels of Matrix Metalloproteinase 9 (MMP-9) by Mediating Its Cellular Catabolism* , 2001, The Journal of Biological Chemistry.

[33]  L. Graham,et al.  Effect of protein synthesis inhibition by cycloheximide on lymphocyte circulation. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[34]  K. Hultenby,et al.  T lymphocyte infiltration of two- and three-dimensional collagen substrata by an adhesive mechanism. , 1993, Experimental cell research.

[35]  C. Ferran,et al.  IN VIVO CELL ACTIVATION FOLLOWING OKT3 ADMINISTRATION: SYSTEMIC CYTOKINE RELEASE AND MODULATION BY CORTICOSTEROIDS , 1990, Transplantation.

[36]  K. Sundqvist,et al.  Induction of motility and alteration of surface membrane polypeptides in lymphocytes by contact with autologous and allogeneic fibroblasts. , 1987, Experimental cell research.

[37]  K. Sundqvist,et al.  A labile antigen complex at the lymphocyte surface: the effect of the substratum on its expression. , 1987, Journal of immunology.

[38]  K. Sundqvist,et al.  Anchorage and lymphocyte function: collagen and the maintenance of motile shape in T cells. , 1986, Immunology.

[39]  H. Mellstedt,et al.  Compartment Dependence of T‐Lymphocyte Motility , 1986, Scandinavian journal of immunology.

[40]  P. Wilkinson.  The locomotor capacity of human lymphocytes and its enhancement by cell growth. , 1986, Immunology.

[41]  Sheldon Penman,et al.  Protein synthesis requires cell-surface contact while nuclear events respond to cell shape in anchorage-dependent fibroblasts , 1980, Cell.

[42]  J. Herz,et al.  Signaling through LRP1: Protection from atherosclerosis and beyond. , 2011, Biochemical pharmacology.

[43]  K. Hultenby,et al.  Infiltrative capacity of T leukemia cell lines: A distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) , 2004, Clinical & Experimental Metastasis.