Unidirectional, heterologous desensitization of the pertussis toxin receptor by the CD3/TCR complex.
Prolonged exposure of many types of receptors to their cognate agonists can lead to a progressive lack of responsiveness. When this occurs after stimulation by the primary agonist for a given receptor it is termed homologous desensitization, and heterologous desensitization when to an agonist binding to a different type of receptor. Pertussis toxin (PTx) is a potent mitogen for human T lymphocytes. We have previously identified the human T cell PTx receptor (PTx-R) as a 43-kDa plasma membrane protein that, when stimulated, leads to the production of the intracellular second messengers, inositol-1,4,5-triphosphate, 1,2-sn-diacylglycerol, and elevated cytosolic calcium. The PTx-R appears to require the co-expression of the CD3/TCR complex because mutant cells that lack the AgR, but express the PTx-R, fail to respond to PTx. In this report, we have investigated the relationship between these two receptor systems. Activation of the PTx-R with submaximal concentrations of PTx did not affect the ability of an anti-CD3 antibody combined with rabbit anti-mIg to stimulate increases in intracellular free calcium concentration [Ca2+]i or diacylglycerol in human peripheral blood T cells. However, treatment with soluble anti-CD3 mAb, which lead to only a modest increase in [Ca2+]i, completely inhibited the effect of PTx. The cells were not refractory to further stimulation of the AgR because cross-linking with rabbit anti-mIg resulted in the standard maximal stimulation. This effect could be observed within 1 min of treatment with anti-CD3 mAb, and persisted for at least 1 h. The effect was not caused by production of either diacylglycerol (leading to activation of PK-C) or an increase in [Ca2+]i by anti-CD3 mAb because the effect could not be mimicked by either phorbol esters or a calcium ionophore. Pretreatment of either resting T lymphoblasts or PBL with anti-CD3 mAb also prevented enhanced [3H]TdR incorporation stimulated by PTx. These observations suggest a model in which T cells can regulate amplification of a non-AgR stimulatory pathway by heterologous desensitization.
Rosoff
P M
PM
Department of Pediatrics (Hematology-Oncology), New England Medical Center, Boston, MA.
Mohan
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C
D002118:Calcium / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D006801:Humans; D016853:Muromonab-CD3 / Q000276:immunology; D037342:Pertussis Toxin; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D011975:Receptors, Mitogen / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D004075:Diglycerides; D016853:Muromonab-CD3; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011975:Receptors, Mitogen; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D002118:Calcium