Constitutive activation of Lck and Fyn tyrosine kinases in large granular lymphocytes infected with the γ‐herpesvirus agents of malignant catarrhal fever

Abstract

SUMMARYLarge granular lymphocytes (LGL) with a T or natural killer (NK) lymphoblast morphology and indiscriminate (non-major histocompatibility complex-linked) cytotoxicity for a variety of target cells can be derived in culture from the tissues of animals infected with either alcelaphine herpesvirus-1 (AlHV-1) or ovine herpesvirus-2 (OvHV-2). In this study, LGL survival in the absence of exogenous interleukin-2 was inhibited by the protein kinase inhibitor genestein, but not the p70 s6 kinase inhibitor rapamycin. Constitutive activation of the src kinases Lck and Fyn was demonstrated in a bovine LGL line infected with OvHV-2 and in two rabbit LGL lines infected with AlHV-1. The p44 erk1 and p42 erk2 mitogen-activated protein kinases (MAPK) were also constitutively activated in the LGLs but not control T cells. Lck and Fyn kinase activity in the LGLs did not increase after mitogen (concanavalin A or concanavalin A plus phorbol ester) stimulation of the cells, in contrast to control T cells. Control T cells, but not the LGLs, proliferated after mitogen stimulation. An analysis of tyrosine phosphorylated proteins in the cells indicated that the LGLs exhibited some similarities and differences to activated control T cells. The results demonstrate that the activated phenotype of the LGLs, associated with malignant catarrhal fever virus infection and in the absence of exogenous interleukin-2, involves constitutively activated Lck and Fyn kinases. These are normally crucial for the initial activation of T cells via several cellsurface receptors (e.g. the T-cell receptor and CD2). The inability of the LGLs to proliferate in response to mitogen may be due to an inability of Lck and Fyn to become further activated after mitogen stimulation.

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

“…Indeed, a causative role for infections with herpes viruses has already been postulated in the pathogenesis of LGL expansions. 47 The elevated cytokine/chemokine levels in LGL patients could therefore indicate a higher degree of viral antigen-driven cellular immune activation enhanced by an intrinsic dysregulation of homeostasis. Consistent with these ideas, we observed the highest levels of IP-10, IL-6, MIG and IL-2R in the plasma of LGL patients with symptomatic CMV reactivation.…”

Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia

“…Although to date, no particular virus has been singled out, human T lymphotropic virus type 1 (HTLV-1) or a related lymphotropic retrovirus and the γ-herpesvirus family [especially human herpesvirus 8 (HHV-8)] are interesting candidates [58][59][60][61][62]. These viruses are clinically associated with hematologic malignancies, show lymphotropic activity, and most importantly, modulate a number of genes that were differentially expressed in our cohort of LGL patients [52,53,57,63].…”

Ex Vivo Bioluminescence Detection of Alcelaphine Herpesvirus 1 Infection during Malignant Catarrhal Fever

“…WD-MCF has been described as a combination of lymphoproliferation and degenerative lesions caused by unknown mechanisms (33,37,39). Recently, we demonstrated that WD-MCF in rabbits is associated with a severe proliferation of CD8 ϩ T cells in peripheral blood mononuclear cells (PBMC) and lymphoid organs (12).…”