Suppression of Acute Anti-Friend Virus CD8⁺T-Cell Responses by Coinfection with Lactate Dehydrogenase-Elevating Virus

Abstract

Friend virus (FV) and lactate dehydrogenase-elevating virus (LDV) are endemic mouse viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8 ؉ T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

“…It has also become clear that FV stocks used in the previous studies were contaminated with LDV, which compromises CD8 + T cell responses (27). To thoroughly investigate the potential factors that influence the onset of virus-specific CD8 + T cell responses following FV infection in the absence of LDV, we compared the Agspecific CD8 + T cell responses elicited by FV infection or injection of FBL3 tumor cells, a highly immunogenic murine leukemia cell line induced in a B6 mouse by F-MuLV (39).…”

“…One question is whether virus-specific CD8 + T cells contribute to the early control of FV in vivo. Although previous studies demonstrated that the depletion of CD8 + T cells significantly accelerated the acute splenomegaly (65)(66)(67), the FV stock used in these studies had been contaminated with LDV, a potent suppressor of CD8 + T cell responses (27). Using the LDV-free FV stock, we confirmed an exacerbated acute splenomegaly in CD8 + T cell-depleted animals upon FV infection (S. Takamura, S. Tsuji-Kawahara, and M. Miyazawa, unpublished observations), which seems to conflict with our current observations regarding the early loss of FV-specific CD8 + T cell function.…”

“…Because these studies did not take into consideration the potentially differential priming conditions (e.g., Ag doses and inflammatory stimuli between the acute and memory phases of FV infection and the stages of CD8 + T cell differentiation from effector to memory), it is unclear whether the dysfunction of FV-specific CD8 + T cells is due solely to the presence of virus-induced Treg cells, as is when and how FV-specific CD8 + T cells suffer functional defects throughout the entire course of FV infection. Furthermore, it has been confirmed that the FV stocks used in the above-reported studies were contaminated with lactate dehydrogenase-elevating virus (LDV), which has been shown to rapidly induce polyclonal T and NK cell activation and enhance Treg cell activities, resulting in delayed and suppressed FVspecific CD8 + T cell responses (27). Taken together, understanding the precise mechanisms and the time course of virus-specific CD8 + T cell dysfunction using LDV-free FV complex is required to fully elucidate the immune evasion strategy of FV.…”

Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8 + T cells and reduces chronic retroviral set points

“…(B10 × A.BY) F1 mice (Th1.2) were chronically infected with 1,500 spleen focus-forming units of FV/lactate dehydrogenaseelevating virus as described (45) and then adoptively transferred with 10 6 Thy1.1 CD8 + T cells from virus-specific TCR Tg mice (15). Seven days after adoptive transfer, Thy1.1 donor cells were sorted from the spleen using a FACSAria cell sorter (Becton Dickinson).…”

CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells

“…injection of 1500 spleen focus-forming units of uncloned virus stock containing B-tropic F-MuLV and polycythemia-inducing spleen focus-forming virus. As previously described, the FV complex also contains lactate dehydrogenase-elevating virus (4,22). Mice were considered chronically infected at 8 wk postinfection.…”