Schiff base-mediated co-stimulation primes the T-cell-receptor-dependent calcium signalling pathway in CD4 T cells

Immunology. 2001 Sep;104(1):50-7. doi: 10.1046/j.1365-2567.2001.01290.x.


In addition to macromolecular interactions that provide co-stimulation during antigen-presenting cell (APC) and CD4+ T-cell conjugation, covalent chemical events between specialized ligands have been implicated in T-cell co-stimulation. These take the form of transient Schiff base formation between carbonyls and amines expressed on APC and T-cell surfaces. Small Schiff base-forming molecules, such as tucaresol, can substitute for the physiological donor of carbonyl groups and provide co-stimulation to T cells, thereby functioning as orally active immunopotentiatory drugs. The Schiff base co-stimulatory pathway in T cells has been partially characterized in terms of changes in Na+ and K+ transport, and activation of the mitogen activated protein kinase (MAPK) ERK2. In the present study, the effects of Schiff base co-stimulation by tucaresol on the T-cell receptor (TCR)-dependent pathway leading to Ca2+ release were investigated. Schiff base co-stimulation by tucaresol was found to prime for enhanced TCR-dependent phospholipase C-gamma phosphorylation, inositol 1,4,5-triphosphate production, and Ca2+ mobilization that correlated with functional enhancement of interleukin-2 production in primary T cells. The effects on Ca2+ occurred comparably in Jurkat and primary CD4+ T cells responding to anti-CD3 monoclonal antibody. Enhancement of the Ca2+ response required a 10-min priming period and was prevented by prior covalent ligation of cell-surface free amino groups by sulpho-N-hydroxy succinimido-biotin; clofilium-mediated inhibition of tucaresol-induced changes in intracellular K+; and selective inhibition of the MAPK pathway. The data are consistent with a priming mechanism in which late co-stimulation-triggered events exert a positive influence on early TCR-triggered events. In additional studies of murine T cells expressing trans-gene TCRs, tucaresol was likewise shown to prime for enhanced Ca2+ mobilization in response to physiological TCR-engagement by MHC-peptide complexes.

MeSH terms

  • Amines / antagonists & inhibitors
  • Animals
  • Benzaldehydes / immunology
  • Benzoates / immunology
  • CD3 Complex / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • Calcium / metabolism*
  • Cell Culture Techniques
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interleukin-2 / biosynthesis
  • Isoenzymes / metabolism
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Phospholipase C gamma
  • Phosphorylation
  • Potassium Channel Blockers
  • Receptors, Antigen, T-Cell / immunology*
  • Schiff Bases / immunology*
  • Type C Phospholipases / metabolism


  • Amines
  • Benzaldehydes
  • Benzoates
  • CD3 Complex
  • Enzyme Inhibitors
  • Interleukin-2
  • Isoenzymes
  • Potassium Channel Blockers
  • Receptors, Antigen, T-Cell
  • Schiff Bases
  • Mitogen-Activated Protein Kinase Kinases
  • Type C Phospholipases
  • Phospholipase C gamma
  • tucaresol
  • Calcium