1alpha,25-dihydroxyvitamin D3 activates T cells of tumor bearers through protein phosphatase 2A.
The sterol 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] can inhibit T cell activation as well as restore the functional competence of suppressed T cells, The present studies determined whether 1,25(OH)2D3 had a differential effect on the activation of normal T cells or of suppressed T cells from mice bearing Lewis lung carcinoma tumors. Normal spleen cell proliferation in response to immobilized anti-CD3 was unaffected by the lower doses of 0.1-10 nM 1,25(OH)2D3, and was inhibited by the higher dose of 100 nM 1,25(OH)2D3. In contrast, 1,25(OH)2D3 increased proliferation and interferon gamma secretion by T cells of tumor bearers in response to stimulation through T cell receptor/CD3. Assessment of mechanisms associated with the 1,25(OH)2D3 stimulation of tumor-bearer T cells implicated protein phosphatase 2A (PP-2A). First, PP-2A activity of spleen cells from tumor bearers was reduced compared to that of normal spleen cells but was increased by 1,25(OH)2D3. Second, 1,25(OH)2D3 stimulation of tumor-bearer T cell proliferation was dependent on this PP-2A activity as it was blocked by doses of okadaic acid that selectively inhibit PP-2A. These results suggest that 1,25(OH)2D3 preferentially enhances the responsiveness of immunosuppressed T cells from tumor bearers to TCR/CD3 stimulation by restoring PP-2A activity.
Wiers
K M
KM
Research Service, Hines VA Hospital, IL 60141, USA.
Lozano
Y
Y
Messingham
K A
KA
Metz
R J
RJ
Young
M R
MR
D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002117:Calcitriol / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002117:Calcitriol