Initial phase I and II clinical trials with recombinant human interleukin-12 have demonstrated the therapeutic efficacy of this cytokine in early stage cutaneous T cell lymphoma as compared with more advanced stages such as the leukemic Sézary syndrome. In an effort to optimize the use of recombinant human interleukin-12, using flow cytometry we studied the regulation of the interleukin-12 receptor β1 (high affinity chain) and β2 (chain necessary for interleukin-12 signal transduction) on normal volunteer CD4⁺ and CD8⁺ T cells and CD4⁺ and CD8⁺ cells from eight patients with different degrees of leukemic involvement with Sézary syndrome. The β1 chain was not readily detectable on resting normal and T cells from Sézary patients, but expression was induced following T cell activation with phytohemagglutinin. Similarly, the β2 chain was not detectable on resting normal volunteer T cells, but could be induced following phytohemagglutinin stimulation. Moreover, the β2 chain on normal volunteer T cells was markedly upregulated following short-term culture with interferon-γ or recombinant human interleukin-12. CD8⁺ T cells routinely exhibited a greater expression of β2 than did CD4⁺ T cells. In marked contrast, both CD4⁺ and CD8⁺ T cells from patients with Sézary syndrome and a high tumor cell burden (> 50% circulating atypical Sézary T cells) failed to express the β2 chain under any culture conditions. Although, culture with anti-interleukin-10 also markedly increased β2 expression on normal volunteer T cells, this failed to induce expression on either CD4⁺ or CD8⁺ T cells from Sézary patients and a high tumor burden. Investigation of patients with Sézary syndrome and a low tumor cell burden (< 15% circulating Sézary T cells) revealed a pattern of β2 expression that was intermediate between advanced Sézary syndrome and normal volunteers. Both CD4⁺ and CD8⁺ peripheral blood T cells from these earlier stage patients were induced to express the β2 chain, although at a lower frequency of positivity than T cells from normals, following culture with phytohemagglutinin, interferon-γ, recombinant human interleukin-12, or anti-interleukin-10. These results indicate that short-term culture with interferon-γ and recombinant human interleukin-12 potently upregulates β2 chain expression on T cells from normal volunteers, whereas a similar, but less marked effect occurs on T cells from Sézary syndrome patients and a low circulating tumor cell burden. In contrast, the β2 chain appears to be suppressed on both CD4⁺ and CD8⁺ T cells from Sézary patients with a heavy circulating tumor cell burden and it is not induced by interferon-γ or recombinant human interleukin-12. Therefore, recombinant human interleukin-12 is likely to be most effective for early stage cutaneous T cell lymphoma due to a greater display of β2 receptors on responding CD8⁺ anti-tumor cytotoxic T cells.