B-Lymphocyte Proliferation during Bovine Leukemia VirusInduced Persistent Lymphocytosis Is Enhanced by T-Lymphocyte-Derived Interleukin-2

Abstract

Bovine leukemia virus (BLV)-induced persistent lymphocytosis is characterized by a polyclonal expansion of CD5+ B lymphocytes. To examine the role of the cytokine microenvironment in this virus-induced B-lymphocyte expansion, the expression of interleukin-2 (IL-2), IL-4, IL-10, and gamma interferon (IFN-γ) mRNA, was measured in stimulated peripheral blood mononuclear cells from persistently lymphocytotic BLV-infected cows, nonlymphocytotic BLV-infected cows, and uninfected cows. IL-2 and IL-10 mRNA expression and IL-2 functional activity were significantly increased when peripheral blood mononuclear cells from persistently lymphocytotic cows were stimulated with concanavalin A (ConA). Additionally, during persistent lymphocytosis, peak IL-2 and IL-10 mRNA expression was delayed, and elevated expression was prolonged. To determine the potential biologic importance of increased IL-2 and IL-10 expression, the response of isolated B lymphocytes from persistently lymphocytotic cows to human recombinant cytokines and to cytokine-containing supernatants from isolated T lymphocytes was examined. While recombinant human IL-10 (rhIL-10) did not consistently induce detectable changes, rhIL-2 increased viral protein (p24) and IL-2 receptor expression in isolated B lymphocytes from persistently lymphocytotic cows. Additionally, rhIL-2 and supernatant from ConA-stimulated T lymphocytes enhanced B-lymphocyte proliferation. The stimulatory activity of the T-lymphocyte supernatant could be completely inhibited with a polyclonal anti-rhIL-2 antibody. Finally, polyclonal anti-rhIL-2 antibody, as well as anti-BLV antibody, inhibited spontaneous proliferation of peripheral blood mononuclear cells from persistently lymphocytotic cows, demonstrating that the spontaneous lymphoproliferation characteristic of BLV-induced persistent lymphocytosis is IL-2 dependent and antigen dependent. Collectively, these findings strongly suggest that increased T-lymphocyte expression of IL-2 in BLV-infected cows contributes to development and/or maintenance of persistent B lymphocytosis.

Cattle Infected with Bovine Leukaemia Virus may not only Develop Persistent B‐cell Lymphocytosis but also Persistent B‐cell Lymphopenia

“…Freshly prepared B cells from the peripheral blood of PL + cattle showed not only an increased expression of sIgM, MHC II, CD5, CD11b and CD11c, but also of the interleukin-2 (IL-2) receptor (CD25; Matheise et al, 1992;Stone et al, 1994). It could be shown that in PL + animals, activated T cells produce IL-2 to a higher level than normal, contributing to the proliferation of CD5 + B cells (Trueblood et al, 1998). Furthermore, an increase in the IL-10 level has been detected in PL + cattle (Pyeon et al, 1996;Pyeon and Splitter, 1999;Yakobson et al, 2000).…”

Bovine CD4+T-Lymphocyte Clones Specific for Rhoptry-Associated Protein 1 ofBabesia bigeminaStimulate Enhanced Immunoglobulin G1 (IgG1) and IgG2 Synthesis

“…IL-2 augments antigen-induced proliferation by Th cell clones, using either PBMC or B cells as APC (references 7 and 12 and data not shown). Furthermore, IL-2 supports the survival of murine germinal center B cells in culture (17) and proliferation of bovine peripheral blood B cells (59).…”

Bovine Leukemia Virus-Induced Persistent Lymphocytosis in Cattle Does Not Correlate with Increased Ex Vivo Survival of B Lymphocytes

“…In this model, cytokines, like interleukin-2 (IL-2) and IL-10, could be implicated in the regulation of apoptosis during leukemogenesis (12,17,21). For example, significant IL-2 functional activity has been observed in concanavalin A-stimulated PBMCs from PL cows (29). Nevertheless, in our hands, a polyclonal anti-recombinant human IL-2 antibody, which was shown to efficiently inhibit bovine IL-2 activity, was unable to abolish the antiapoptotic effect of culture supernatants from unstimulated cells isolated from cattle with PL (data not shown).…”