1-ALPHA,25-DIHYDROXYVITAMIN D3 ACTIVATES T-CELLS OF TUMOR BEARERS THROUGH PROTEIN PHOSPHATASE 2A

The sterol 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] can inhibi t T cell activation as well as restore the functional competence of su ppressed T cells. The present studies determined whether 1,25(OH)(2)D- 3 had a differential effect on the activation of normal T cells or of suppressed T cells from mice bearing Lewis lung carcinoma tumors. Norm al spleen cell proliferation in response to immobilized anti-CD3 was u naffected by the lower doses of 0.1-10 nM 1,25(OH)(2)D-3, and was inhi bited by the higher dose of 100 nM 1,25(OH)(2)D-3. In contrast, 1,25(O H)(2)D-3 increased proliferation and interferon gamma secretion by T c ells of tumor bearers in response to stimulation through T cell recept or/CD3. Assessment of mechanisms associated with the 1,25(OH)(2)D-3 st imulation of tumor-bearer T cells implicated protein phosphatase 2A (P P-2A). First, PP-2A activity of spleen cells from tumor bearers was re duced compared to that of normal spleen cells but was increased by 1,2 5(OH)(2)D-3. Second, 1,25(OH)(2)D-3 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)(2)D-3 preferentially enhances the responsivenes s of immunosuppressed T cells from tumor bearers to TCR/CD3 stimulatio n by restoring PP-2A activity.