title: Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma.
abstract: Using biopsy specimens from patients with B-cell non-Hodgkin's lymphoma, we observed a significantly low frequency of T(H)17 cells, including several samples with no detectable amount of interleukin (IL)-17-producing cells present in the tumor microenvironment. We found that, in the absence of lymphoma B cells, treatment with IL-1beta/IL-6 or lipopolysaccharide (LPS) enhanced IL-17 expression in CD4(+) T cells and this enhancement was attenuated when CD4(+) T cells were cocultured with lymphoma B cells. Blockade of CD27-CD70 or CD28-CD80/86 interactions by anti-CD70 or anti-CD80/86 antibodies restored LPS-mediated induction of IL-17 expression in CD4(+) T cells cocultured with lymphoma B cells. Because a subset of lymphoma B cells express IL-2 and given that IL-2 signaling is critically important in the development of regulatory T (T(reg)) cells, we tested the role of IL-2 signaling in T(H)17 cell development. We found that treatment with anti-IL-2 antibody to interrupt IL-2 signaling significantly inhibited Foxp3 expression in CD4(+) T cells. In contrast, interruption of IL-2 signaling up-regulated IL-17 expression in CD4(+) T cells and restored lymphoma-mediated down-regulation of IL-17-producing cells. Furthermore, the reversal of T(reg) cell activity by LPS or CpG-A resulted in an enhancement of IL-17-producing cells. Taken together, our study indicated that lymphoma B cells play an important role in skewing the balance between T(reg) and T(H)17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Zhi-Zhang
authors.initials: ZZ
authors.lastname: Yang
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ziesmer
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000502:physiology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D053759:Interleukin-23 / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D007376:Interleukin-2; D053759:Interleukin-23; D016212:Transforming Growth Factor beta