Dysregulation of lymphocyte interleukin-12 receptor expression in Sezary syndrome

Initial phase I and II clinical trials with recombinant human interleukin-1 2 have demonstrated the therapeutic efficacy of this cytokine in early stag e cutaneous T cell lymphoma as compared with more advanced stages such as t he leukemic Sezary syndrome. In an effort to optimize the use of recombinan t human interleukin-12, using flow cytometry we studied the regulation of t he interleukin-12 receptor beta1 thigh affinity chain) and beta2 (chain nec essary for interleukin-12 signal transduction) on normal volunteer CD4(+) a nd CD8(+) T cells and CD4(+) and CD8(+) cells from eight patients with diff erent degrees of leukemic involvement with Sezary syndrome, The beta1 chain was not readily detectable on resting normal and T cells from Sezary patie nts, but expression was induced following T cell activation with phytohemag glutinin, Similarly, the beta2 chain was not detectable on resting normal v olunteer T cells, but could be induced following phytohemagglutinin stimula tion. Moreover, the beta2 chain on normal volunteer T cells was markedly up regulated following short-term culture with interferon-gamma or recombinant human interleukin-12, CD8(+) T cells routinely exhibited a greater express ion of beta2 than did CD4(+) T cells. In marked contrast, both CD4(+) and C D8(+) T cells from patients with Sezary syndrome and a high tumor cell burd en (> 50% circulating atypical Sezary T cells) failed to express the beta2 chain under any culture conditions. Although, culture with anti-interleukin -10 also markedly increased beta2 expression on normal volunteer T cells, t his failed to induce expression on either CD4(+) or CD8(+) T cells from Sez ary patients and a high tumor burden, Investigation of patients with Sezary syndrome and a low tumor cell burden (< 15% circulating Sezary T cells) re vealed a pattern of <beta>2 expression that was intermediate between advanc ed Sezary syndrome and normal volunteers. Both CD4(+) and CD8(+) peripheral blood T cells from these earlier stage patients were induced to express th e beta2 chain, although at a lower frequency of positivity than T cells fro m normals, following culture with phytohemagglutinin, interferon-gamma, rec ombinant human interleukin-12, or anti-interleukin-10, These results indica te that short-term culture with interferon-gamma and recombinant human inte rleukin-12 potently upregulates beta2 chain expression on T cells from norm al volunteers, whereas a similar, but less marked effect occurs on T cells from Sezary syndrome patients and a low circulating tumor cell burden, In c ontrast, the beta2 chain appears to be suppressed on both CD4(+) and CD8(+) T cells from Sezary patients with a heavy circulating tumor cell burden an d it is not induced by interferon-gamma or recombinant human interleukin-12 . Therefore, recombinant human interleukin-12 is likely to be most effectiv e for early stage cutaneous T cell lymphoma due to a greater display of bet a2 receptors on responding CD8(+) anti-tumor cytotoxic T cells.