SEZARY LINEAGE CELLS CAN BE INDUCED TO PROLIFERATE VIA CD28-MEDIATED COSTIMULATION

Sezary syndrome and mycosis fungoides are related chronic lymphoprolif erative diseases caused by the malignant growth of CD4(+) T lymphocyte s that display hyperconvoluted nuclei and a predilection for skin homi ng. Despite the malignant nature of these cells, they paradoxically do not grow in vitro, either spontaneously or following exposure to mito gens. Partly because of this technical limitation, the cellular lineag e and causes of abnormal growth resulting in a classical hyperconvolut ed Sezary cell are poorly characterized. To better understand these as pects, we examined Sezary lineage cell growth in vitro. We found that, contrary to previous reports, Sezary lineage cells are capable of in vitro proliferation in response to either PHA or anti-CD3 mAb, if exog enous costimulation is provided. The CD28-B7 interaction provides at l east one of the costimulatory signals capable of inducing Sezary linea ge cell growth. Namely, Sezary lineage cells from three of six Sezary syndrome patients proliferated in response to PHA if an anti-CD28 mAb was also added to the in vitro culture. The remaining three patients' Sezary lineage cells were dependent upon CD28-B7-mediated costimulatio n, but in addition required other intercellular signals present on blo od mononuclear cells. The relative lack of costimulation from the pati ents' own PBMC is not due to an intrinsic defect in the mycosis fungoi des/Sezary syndrome patients' immune accessory; cells. Rather, it appe ars primarily due to an inability of Sezary cells to significantly up- regulate CD40 ligand (gp39) following in vitro exposure to PHA.