Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

Abstract

Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virusspecific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection

“…This may be somewhat expected given that T cells rely on a preformed TCR repertoire that cannot mutationally evolve during antigenic challenges. This is in contrast to the B cell response, which relies upon antibody sequence diversification through somatic hypermutations such that repertoires dramatically diverge between hosts to eventually attain "personalized" neutralization capacities after months of infection (Staupe et al, 2019;Kräutler et al, 2020).…”

Profiling Virus-Specific Tcf1+ T Cell Repertoires During Acute and Chronic Viral Infection

“…This may be somewhat expected given that T cells rely on a preformed TCR repertoire that cannot mutationally evolve during antigenic challenges. This is in contrast to the B cell response, which relies upon antibody sequence diversification through somatic hypermutations such that repertoires dramatically diverge between hosts to eventually attain "personalized" neutralization capacities after months of infection (4,20).…”

Vectored antibody gene delivery restores host B and T cell control of persistent viral infection

“…The mechanisms underlying augmented antiviral GC B cell responses in VAGD-treated mice require further investigation. Several not mutually exclusive mechanisms may contribute, including the direct beneficial effects of reduced viral antigen loads on GC reactions (Staupe et al, 2019), conformational epitope unmasking on antibody-bound antigens (Hioe et al, 2009;Kumar et al, 2013), and improved delivery and/or retention of antibody-bound viral antigen by Fcg and complement receptors inside GCs (Batista and Harwood, 2009;Carroll and Isenman, 2012;Phan et al, 2009).…”

“…Our study has not, however, addressed the potential effect of VAGD on Tfh subset differentiation and functionality, such as the possibility of an augmented proportion of Tfh cells co-producing IL-21 and IL-10 (Xin et al, 2018). The effects of VAGD on systemic viral antigen loads, conformationally altered viral antigen display, and viral antigen targeting to GCs have been discussed above for their potential effect on antiviral B cells (Batista and Harwood, 2009;Carroll and Isenman, 2012;Hioe et al, 2009;Kumar et al, 2013; Phan et al, Staupe et al, 2019), but they also may directly and/or indirectly affect Tfh profiles, thus ultimately culminating in the augmented GC B cell responses observed. In contrast to Tfh cells and for currently unknown reasons, however, we failed to observe a clear effect of VAGD on cytokine-secreting Th1 responses as reported from SIV-infected NHPs (Yamamoto et al, 2009).…”