CD3 hyporesponsiveness and in vitro apoptosis are features of T cells from both malignant and nonmalignant secondary lymphoid organs.
There is a dogma in tumor immunology that tumor-infiltrating lymphocytes (TIL) are defective based on their lack of antitumoral efficacy in vivo and on impaired response to in vitro functional tests. However, TIL have been compared usually with peripheral blood T lymphocytes, raising doubts on the conclusions drawn. Therefore, we compared TIL from B cell non-Hodgkin's lymphomas (NHL) with T cells from nonmalignant secondary lymphoid organs. NHL-TIL were unresponsive to activation by immobilized anti-CD3 mAb, although bypassing T cell receptor (TCR)/CD3 signaling led to proliferation. The poor proliferative responses of NHL-TIL could not be explained by quantitative defects in TCRzeta expression. NHL-TIL underwent marked spontaneous apoptosis in vitro with loss of approximately 50% of cells after 24 h of culture. This was associated with downregulation of the antiapoptotic Bcl-xL and Bcl-2 proteins, whereas viable NHL-TIL maintained their expression. IL-2, anti-CD3/IL-2, and manipulation of the Fas/Fas-ligand death pathway had no effect on NHL-TIL survival. Apoptosis was not due to increased cell cycling, as NHL-TIL were quiescent, nonproliferating cells. T cells from inflammatory, nonmalignant tissues gave similar functional results to NHL-TIL, suggesting the existence of factors common to the microenvironment of these diverse pathologies. Thus, the quiescent, anergic phenotype of NHL-TIL cannot be attributed solely to tumor factors, but rather is a feature of T cells from chronic inflammatory lesions.
Agrawal
S
S
Department of Immunology, and INSERM Research Units, France.
Marquet
J
J
Delfau-Larue
M H
MH
Copie-Bergman
C
C
Jouault
H
H
Reyes
F
F
Bensussan
A
A
Farcet
J P
JP
D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology*; D002453:Cell Cycle; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007700:Kinetics; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D017252:CD3 Complex; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D051020:bcl-X Protein