Nucleoprotein‐specific nonneutralizing antibodies speed up LCMV elimination independently of complement and FcγR

Abstract

CD8 + T cells have an essential role in controlling lymphocytic choriomeningitis virus (LCMV) infection in mice. Here, we examined the contribution of humoral immunity, including nonneutralizing antibodies (Abs), in this infection induced by low virus inoculation doses. Mice with impaired humoral immunity readily terminated infection withthe slowly replicating LCMV strain Armstrong but showed delayed virus elimination after inoculation with the faster replicating LCMV strain WE and failed to clear the rapidly replicating LCMV strain Docile, which is in contrast to the results obtained with wild-type mice. Thus, the requirement for adaptive humoral immunity to control the infection was dependent on the replication speed of the LCMV strains used. Ab transfers further showed that LCMV-specific IgG Abs isolated from LCMV immune serum accelerated virus elimination. These Abs were mainly directed against the viral nucleoprotein (NP) and completely lacked virus neutralizing activity. Moreover, mAbs specific for the LCMV NP were also able to decrease viral titers after transfer into infected hosts. Intriguingly, neither C3 nor Fcγ receptors were required for the antiviral activity of the transferred Abs. In conclusion, our study suggests that rapidly generated nonneutralizing Abs specific for the viral NP speed up virus elimination and thereby may counteract T-cell exhaustion. Keywords: CD8 + T cells · Fc gamma receptors · Humoral immunity · LCMV-binding antibodies See accompanying article by Richter and OxeniusAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionChronic infections with non-or poorly cytopathic viruses like HCV and HIV affect several hundred million of people worldwide. ToCorrespondence: Prof. Hanspeter Pircher e-mail: hanspeter.pircher@uniklinik-freiburg.de combat these infections, T cells are essential; however, the role of humoral immunity is less clear. Inoculation of mice with lymphocytic choriomeningitis virus (LCMV) is a well-established animal model to study immunological effector mechanisms in infection with a prototypic noncytopathic virus. To control LCMV infection in mice, CD8 + T cells are required. B-cell-deficient mice have been used by many groups to investigate the role of humoral C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2338-2348 Immunity to infection 2339 immunity in the LCMV infection model. The first experiments performed with such mice showed that virus elimination and generation of memory CD8 + T cells were not altered in the absence of B cells [1]. When higher virus infection doses and other viral strains were used, virus clearance was, however, impaired [2][3][4]. In other studies, recrudescence of viremia after initial virus clearance was observed months after infection, and memory T cells from long-term LCMV-infected B-cell-deficient mice were reported to be less efficient in adoptive immunotherapy [5,6]. The conclusions of these studies in B-cell-defi...

Non‐neutralizing antibodies protect from chronic LCMV infection independently of activating FcγR or complement

“…The experiments shown here do not propose a role for activating FcγR or complement for the effector functions exerted by LCMV‐binding antibodies, which is also corroborated by the results of Straub et al . We cannot rule out though that the presence of complement and FcγR can mutually compensate for each other; however, the protective effect of non‐neutralizing antibody transfer was also apparent in mice deficient for both FcRγ and C3 . Likewise, FcγRIIB, which is not targeted in FcRγ −/− mice, could be involved in the antiviral protection mediated by antibodies.…”

“…Furthermore, Fc receptors can mediate phagocytosis of the virus and potentially lead to its subsequent destruction by Fc receptor mediated activation of the innate immune system or antibody‐dependent cellular cytotoxicity . The experiments shown here do not propose a role for activating FcγR or complement for the effector functions exerted by LCMV‐binding antibodies, which is also corroborated by the results of Straub et al . We cannot rule out though that the presence of complement and FcγR can mutually compensate for each other; however, the protective effect of non‐neutralizing antibody transfer was also apparent in mice deficient for both FcRγ and C3 .…”

“…Comparable findings are reported in the study by Straub et al. , showing that transfer of non‐neutralizing antibodies at early time points of LCMV infection accelerates virus control in vivo.…”

Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

“…A similar effect on viral replication in tissues was also observed (Fig 1C). Development of neutralizing antibody titers are delayed after cl13 infection, non-neutralizing antibodies may be important(9, 13, 14) (data not shown) defective FcR function impairs viral control during cl13 infection(15, 16). Thus, non-neutralizing functions of T-bet dependent antibody or B cell responses may play a role in chronic LCMV infection.…”

B Cell Depletion Curtails CD4+ T Cell Memory and Reduces Protection against Disseminating Virus Infection

“…The data in Figure 7 show that B cell-depletion impairs immunity to disseminating virus infection, implying that B cells directly or indirectly contribute factors that prevent T cell exhaustion. B cell production of cytokines or antibody may contribute to the resolution of infection (76, 94, 95). Overall, our findings suggest that B cell-depletion therapies in people will increase their susceptibility to opportunistic infections.…”