Age-associated B cells are long-lasting effectors that impede latent gHV68 reactivation

Abstract

Age-associated B cells (ABCs; CD19+CD11c+T-bet+) are a unique population that are increased in an array of viral infections, though their role during latent infection is largely unexplored. Here, we use murine gammaherpesvirus 68 (γHV68) to demonstrate that ABCs remain elevated long-term during latent infection and express IFNγ and TNF. Using a recombinant γHV68 that is cleared following acute infection, we show that ABCs persist in the absence of latent virus, though their expression of IFNγ and TNF is decreased. With a fluorescent reporter gene-expressing γHV68 we demonstrate that ABCs are infected with γHV68 at similar rates to other previously activated B cells. We find that mice without ABCs display defects in anti-viral IgG2a/c antibodies and are more susceptible to reactivation of γHV68 following virus challenges that typically do not break latency. Together, these results indicate that ABCs are a persistent effector subset during latent viral infection that impedes γHV68 reactivation.

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS

“…This finding indicates that, in the context EAE, ABCs do not appear to be acting as MOG APCs. We have also previously shown no difference in CD8 T cells specific to γHV68 during latent infection between Ctrl and KO mice (55).…”

Age-associated B cells in autoimmune diseases

“…While autoantibody production often contributes to autoimmune pathogenesis, it is not always required for the development of disease. In the MS disease model EAE, knocking out the ABC population does not alter the serum levels of myelin-specific IgG2a/c [40].…”

“…In non-autoimmune settings, ABCs are detected in the spleen, peripheral blood, and bone marrow, though are rare in lymph nodes and tonsils [17]. The spleen appears to act as the primary ABC reservoir following viral infection [17,40]. There is evidence that ABCs persist long-term in the marginal zone, where they are primed to initiate secondary germinal centres [41].…”

“…ABCs display a female sex bias during aging, with similar proportions of ABCs during youth and adolescence, though increasing in proportion with age more so in females than males [11]. Recently, it has been reported that ABC frequency during viral infection and autoimmunity is increased in females more so than males in adolescent mice, demonstrating that the sex bias is not restricted to aging [25,40,48]. The preferential ABC accumulation in females may be due to the dominant role of TLR7 stimulation in their development; TLR7 is X-linked and partially escapes X-chromosome inactivation, leading to its overexpression in females [78].…”

“…Previously, we have used a murine analog of Epstein-Barr virus, gammaherpesvirus 68, to demonstrate that latent infection results in more severe disease in EAE and collagen-induced arthritis [38,88]. Recently, we demonstrated that ABCs remain elevated and continue to express TNF and IFNγ long-term during latent gammaherpesvirus 68 infection [40]. Therefore, we suggest that latent Epstein-Barr virus infection might stimulate the continued activation of the ABC population, poising them to contribute pathogenically at the onset of autoimmune disease.…”