Progression to persistent lymphocytosis and tumor development in bovine leukemia virus (BLV)-infected cattle correlates with impaired proliferation of CD4+ T cells in response to gag- and env-encoded BLV proteins

Abstract

The mechanism of leukemogenesis and persistent lymphocytosis (PL; benign expansion of B lymphocytes) in cattle infected with bovine leukemia virus (BLV; a retrovirus closely related to human T-cell leukemia virus type 1) is unknown; however, the immune system likely plays an important role in controlling the outcome of infection. In this study, we compared T-cell competence in serologically positive alymphocytotic (AL) animals with T-cell functions in animals with progressive stages of infection, PL and tumor bearing (TB). Dramaticdifferences were observed in lymphocyte proliferation to recombinant proteins encoded by BLV gag (p12, p15, and p24) and env (gp30, and gp51) genes in different disease stages. Lymphocytes from AL cattle recognized an average of three of five recombinant proteins per animal. Expansion of antigen pulsed lymphocytes in interleukin-2 increased protein recognition to almost five per animal. In contrast, lymphocytes from PL and TB animals failed to recognize any BLV recombinant proteins. Short-term T-cell cultures from the PL group expanded in interleukin-2, as well as the PL and TB cells cultured in indomethacin (3 to 6 g/ml), increased the average of recognized proteins per animal to one. Cells proliferating to BLV antigens were CD4 ؉ T lymphocytes, as shown by cell depletion studies. The positive effect of indomethacin suggests involvement of prostaglandin E 2 as a negative regulatory factor in the later stages of disease. Thus, for the first time, advancing stages of BLV infection were correlated with decreased T-cell competence, providing deeper insight into pathogenesis of retroviral infections.

Reduced IL-2 and IL-4 mRNA Expression in CD4+ T Cells from Bovine Leukemia Virus-Infected Cows with Persistent Lymphocytosis

“…We have demonstrated that both Th1 (IL-2) and Th2 (IL-4) cytokine mRNA expression is reduced in the CD4 ϩ T cell subset of BLV ϩ PL ϩ cows and that IFN-␥ mRNA expression might also be down-regulated in the CD8 ϩ T cell compartment. These findings, in conjunction with the observation that CD4 ϩ T cells from cows with PL show a diminished proliferative response to BLV gag and env antigens (Orlik and Splitter, 1996), indicate that the functionality of the CD4 ϩ T cell subset becomes gradually compromised as the disease progresses. The mechanism that results in the apparent down-regulation of IL-2 and IL-4 mRNA expression is at present unclear.…”

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

“…Loss of T-helper function in HIV-infected individuals has been shown to be mediated, at least in part, by . Similarly, the inhibitory effect of IL-10 on bovine T-helper function (4) could partially explain the recently reported decrease in BLV anti-gen-specific proliferation of CD4 ϩ T lymphocytes from persistently lymphocytotic cows (41). Additionally, the ability of IL-10 to downregulate IL-2R, but not IL-2, expression in bovine T lymphocytes (7) suggests a mechanism by which elevated IL-2 could preferentially stimulate proliferation of B lymphocytes without a concurrent increase in T lymphocytes during persistent lymphocytosis.…”

Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

“…The Th1 response is critical for the control of BLV infection. During BLV infection, suppression of both CD4 + T cell proliferation and cytotoxic immune response against BLV Ags is associated with disease progression (13,14). To develop a novel strategy for effective control of BLV infection, our recent studies have examined the detailed mechanisms of immune dysfunction in BLV infection.…”