B‐cell fate decisions following influenza virus infection

Abstract

Rapidly induced, specific Ab generated in extrafollicular foci are important components of early immune protection to influenza virus. The signal(s) that prompt B cells to participate in extrafollicular rather than germinal center responses are incompletely understood. To study the regulation of early B-cell differentiation events following influenza infection, we exploited earlier findings of a strong contribution of C12 idiotype-expressing B cells to the primary HA-specific response against influenza A/PR/8/34. Using an idiotype-specific mAb to C12 and labeled HA, in conjunction with multicolor flow cytometry, we followed the fate of C12Id-expressing influenza HA-specific B cells in WT BALB/c mice, requiring neither genetic manipulation nor adoptive cell transfer. Our studies demonstrate that HA-specific C12Id 1 B cells are phenotypically indistinguishable from follicular B cells. While they induced both extrafollicular and germinal center responses, extrafollicular responses were strongly predominant. Provision of increased HA-specific T-cell help increased the magnitude of the extrafollicular response, but did not shift the C12Id 1 response toward germinal center formation. Collectively the data are consistent with the hypothesis that B-cell fate determination following activation is a stochastic process in which infectioninduced innate signals might drive the preferential expansion of the early extrafollicular response. Key words: B cells . Cell differentiation . Immune responses . Immune regulation IntroductionInfluenza virus infection-induced anti-viral Ab can contribute to survival from primary and secondary infection [1][2][3][4][5][6][7]. Rapid B-cell responses in the local respiratory tract draining mediastinal LN (MedLN) are induced as early as 48-72 h after infection [8]. They contribute to viral clearance during primary infection by neutralizing the virus and reducing influenza virus spread [2,5]. Therefore the events that govern early B-cell activation following influenza virus infection are crucial for ameliorating disease outcome. The mechanisms underlying early B-cell activation, however, are incompletely understood.Rapid Ab production originates from extrafollicular foci developing at the edges of the T-and B-cell zones in secondary lymphoid tissues following antigen exposure. These responses are thought to generate primarily short-lived plasma cells [9]. Rapid Ab production at extrafollicular sites is attributed to T cell-independent as well as T-dependent responses [10,11]. In contrast, the slower intrafollicular germinal center reactions require cognate CD4 T-cell-B-cell interactions [12,13]. They are regarded as the birthplace of long-lived humoral immunity, providing both memory B cells and long-lived plasma cells [11,13]. Both extra and intra-follicular responses develop strongly in the regional LN following influenza virus infection [14].The selection events that underlie the establishment of extrafollicular versus germinal center B-cell responses are important events in the initiation ...

Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection

“…1B). This process resembles the slower accumulation of plasma cells in the lungs after influenza virus infection (11) and may reflect a requirement for structural alteration and/ or niche formation in the infected lungs for B-cell localization. Although definitive markers of murine memory B cells remain to be identified (12,13), CD73, CD80, and CD273 (PD-L2) are expressed at higher levels on splenic memory than on naïve B cells (14,15).…”

Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus

“…The combined CD4 T cell data and serological analysis suggest that an expanded population of primed CD4 T cells can facilitate new B cell responses that have not been encountered before. According to this model, there may be limiting numbers of CD4 T cells capable of providing help during T-B cell interactions, as has recently been suggested by adoptive transfer experiments (50). In addition to providing help during challenge with live infection by the novel virus, helper cells in the memory population of CD4 T cells specific for HA and NA may be critical for "dose-sparing" efforts that are needed for rapid deployment of limited doses of vaccines to novel influenza virus strains (reviewed in references 3, 9, 16, and 54).…”

T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses

“…However, Gal-9 deficiency resulted in higher frequencies of virus-specific CD4 T cells in the airways after influenza infection, consistent with a more vigorous CD4 T-cell response in the draining lymph nodes. The rapidity of the B-cell response in G9KO mice suggests an increase in antibody-secreting cell generation via the extrafollicular pathway of B-cell differentiation, an arm of the B-cell response that is enhanced by increased availability of T-cell help (24). The expression of Tim-3 by activated Th1 but not Th2 cells suggests that the Th1 response may be preferentially enhanced in G9KO mice.…”