Abstract
Murid γ-herpesvirus-4 (MuHV-4) promotes polyclonal B cell activation and establishes latency in memory B cells via unclear mechanisms. We aimed at exploring whether B cell receptor specificity plays a role in B cell susceptibility to viral latency and how this is related to B cell activation. We first observed that MuHV-4-specific B cells represent a minority of the latent population, and to better understand the influence of the virus on non-MuHV-4 specific B cells we used the SWHEL mouse model, which produce hen egg lysozyme (HEL)-specific B cells. By tracking HEL+ and HEL− B cells, we showed that in vivo latency was restricted to HEL− B cells while the two populations were equally sensitive to the virus in vitro. Moreover, MuHV-4 induced two waves of B cell activation. While the first wave was characterized by a general B cell activation, as shown by HEL+ and HEL− B cells expansion and upregulation of CD69 expression, the second wave was restricted to the HEL− population, which acquired germinal center (GC) and plasma cell phenotypes. Antigenic stimulation of HEL+ B cells led to the development of HEL+ GC B cells where latent infection remained undetectable, indicating that MuHV-4 does not benefit from acute B cell responses to establish latency in non-virus specific B cells but relies on other mechanisms of the humoral response. These data support a model in which the establishment of latency in B cells by γ-herpesviruses is not stochastic in terms of BCR specificity and is tightly linked to the formation of GCs.
Highlights
The murid c-herpesvirus-4 (MuHV-4, known as MHV-68 or cHV-68) has led to valuable insights in understanding human cherpesvirus related diseases caused by Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus (KSHV) [1]
Both YFP2 and YFP+ B cells showed a low frequency of virus-specific antibodysecreting cells (ASC) cells when compared to the total ASC
These data indicate that latent infection is not restricted to Murid c-herpesvirus-4 (MuHV-4) specific B cells and that the virus is able to promote the activation of non-virus-specific B cells independently of their infection status
Summary
The murid c-herpesvirus-4 (MuHV-4, known as MHV-68 or cHV-68) has led to valuable insights in understanding human cherpesvirus related diseases caused by Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus (KSHV) [1]. The virus disseminates to secondary lymph organs via serial events of lymphoid/myeloid cellular exchanges [6] where it promotes a CD4-dependent polyclonal B cell response and establishes latency in longlived memory B cells [1,5,7,8]. This polyclonal B cell activation can lead to the emergence of auto-antibodies but MuHV-4 infection is usually not associated with the development of autoimmune diseases or lymphomas in immune competent mice [9]. Antibody-mediated depletion experiments [11,12] as well as work performed on MHC class II deficient mice [13] (which are CD4+ T cells deficient) have led to similar observations, that the absence of CD4+ T cells leads to lower latency levels
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