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IL-21 regulates Th17 cell homeostasis, enhances the differentiation of memory B cells and antibody-secreting plasma cells, and promotes the maintenance of CD8+T-cell responses. In this study, we investigated the phenotype, function, and frequency of blood and intestinal IL-21–producing cells in nonhuman primates that are hosts of progressive (rhesus macaques [RMs]) and nonprogressive (sooty mangabeys [SMs]) SIV infection. We found that, in both species, memory CD4+CD95+CCR6−T cells are the main IL-21 producers, and that only a small fraction of CD4+IL-21+T cells produce IL-17. During chronic SIV infection of RMs, CD4+IL-21+T cells were significantly depleted in both blood and rectal mucosa, with the extent of this depletion correlating with the loss of Th17 cells. Furthermore, treatment with IL-21 increased the in vivo levels of Th17 cells in SIV-infected RMs. In contrast, normal levels of CD4+IL-21+T cells were found in SIV-infected SMs. Collectively, these data indicate that depletion of IL-21–producing CD4+T cells distinguishes progressive from nonprogressive SIV infection of RMs and SMs, and suggest that depletion of CD4+IL-21+T cells is involved in the preferential loss of Th17 cells that is associated with SIV disease progression. Further preclinical studies of IL-21 as a potential immunotherapeutic agent for HIV infection may be warranted.

Recent evidence indicates that Reed-Sternberg (RS) cells from many cases of Hodgkin's disease have features of activated lymphocytes and that lymphokines from activated lymphocytes induce proliferation of L-428 RS cells. It is shown here that a lymphokine similar to a lymphokine secreted by activated lymphocytes is secreted by L-428 cells. This lymphokine has a molecular weight =68,000 daltons, identical to glycosylated recombinant interleukin-4 (rlL-4), and cross-reacts with monoclonal anti-IL-4 in Western immu-noblotting. This Hodgkin's cell growth factor (HCGF) is 100% neutralized by polyclonal anti-IL-4 antibodies and competes for the IL-4 receptor. After acid-elution, the L-428 RS cell has been shown to have 3,396 ± 120 high-affinity receptor sites/cell. HCGF competes with rlL-4 for this receptor and L-428 cells contain mRNA for IL-4. Although all evidence indicates that IL-4 is an important secreted autocrine growth factor for L-428 RS cells, anti-IL-4 has no effect on the sustained serum-free growth of these Hodgkin's cells, suggesting that either the IL-4 receptor and the IL-4 receptor-growth factor complex are protected from antibody inhibition or other mechanisms are responsible for the sustained proliferation of L-428 RS cells.