T Cell Receptor-Mediated Signaling Is Defective in T Cells Obtained from Patients with Primary Intracranial Tumors

Lorri A. Morford, Lucinda H. Elliott, Sonia L. Carlson, William H. Brooks, Thomas L. Roszman

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

It has been well established that patients with malignant glioblastomas exhibit T cell anergy. In this report, we further investigate the nature of this T cell anergy. The results demonstrate that tumor size but not location correlates with decreased mitogen or anti-CD3 mAb responsiveness of T cells obtained from patients. Stimulation of the TCR/CD3 complex on these patients' T cells revealed defects in early transmembrane signaling. Both PHA and anti-CD3 mAb activated PBL and T cells obtained from patients exhibited a marked decrease in the tyrosine phosphorylation of a number of proteins. In particular, decreased phosphorylation of pp100 and phospholipase Cγ1 (PLCγ1) was observed. In addition, PLCγ1 and p56lck protein levels were dramatically reduced in T cells obtained from patients harboring a glioma. In contrast, the protein levels of p59fyn were normal or only slightly reduced in T cells obtained from patients with gliomas. Quantitation of free intracellular calcium concentrations ([Ca2+]i) after mitogen (PHA) stimulation or ionomycin treatment of T cells obtained from patients revealed that they mobilize less calcium than do T cells obtained from normal subjects. Stimulation of T cells obtained from patients with PMA and ionomycin, which should bypass the requirement for PLCγ1 activation as well as directly activate the p21ras signaling pathway, did not restore the proliferative capacity of these T cells to normal levels. These results indicate that the anergy observed in T cells obtained from these patients is a consequence of one or more defects in the early transmembrane signaling events associated with TCR/CD3 stimulation.

Original languageEnglish
Pages (from-to)4415-4425
Number of pages11
JournalJournal of Immunology
Volume159
Issue number9
StatePublished - Nov 1 1997

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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