Early Response to Rotavirus Infection Involves Massive B Cell Activation

Abstract

Rotavirus is an acute enteric pathogen which induces severe diarrhea in infants and children. To determine the immune response to rotavirus in vivo, we used a mouse model of rotavirus infection. We observed dramatic increases in the sizes of both Peyer’s patches and mesenteric lymph nodes, but not spleen, between 1 and 6 days after infection with a homologous strain of murine rotavirus, EC wild type. Histological analysis showed large increases in the numbers of lymphocytes in these same tissues in rotavirus-infected mice. Flow cytometric analysis confirmed the increase in numbers of lymphocytes and revealed a large increase in the percentage of activated B, but not T, lymphocytes in both Peyer’s patches and mesenteric lymph nodes of rotavirus-infected mice compared with control mice. Fragment cultures from these tissues established at 3–4 days postinfection contain rotavirus-specific IgM but not IgA Ab. A similar degree of lymphoid hyperplasia and percentage of activated B cells were observed in rotavirus-infected TCR knockout mice. Taken together, our findings show that rotavirus infection, in the context of a normal immune response, induces a large increase in the percentages of activated B cells in the absence of any detectable increase in the percentage of activated T cells, implicating a T cell-independent B cell response as the primary mechanism for initial rotavirus clearance.

Immunodominance of the VH1–46 Antibody Gene Segment in the Primary Repertoire of Human Rotavirus-Specific B Cells Is Reduced in the Memory Compartment through Somatic Mutation of Nondominant Clones

“…Given the human RV studies showing a high proportion of naive B cells in the RV-specific circulating repertoire (14), the murine model evidence that a large portion of naive B cells expands in the absence of T cell help (7), and the observation of RV-protective Ab production in the TCR knockout mouse (29), it is intriguing to speculate that induction of RV-specific memory B cells occurs in the absence of efficient Th cell activity. Possibly the induction of RV-specific B cells occurs in a unique intestinal compartment independent of germinal centers, or in a unique cytokine milieu in the intestine.…”

“…B cell-derived Ig appears to play a more important role in the protective RV-specific memory response (3)(4)(5)(6). The detection of robust T cell-independent B cell responses in early RV infection in mice implicated B cells as a major determinant of initial RV clearance (7). Furthermore, naive B cells also were shown to be the principal APCs associated with induction of intestinal IgA production after s.c. RV injection in mice (8).…”

Redundant Role of Chemokines CCL25/TECK and CCL28/MEC in IgA+ Plasmablast Recruitment to the Intestinal Lamina Propria After Rotavirus Infection

“…In mice, RV-specific B cells are responsive to CCL25 and CCL28 (10,22), and B cells lacking ␤ 7 are defective in mediating clearance of chronic infection in immune-deficient mice (9). Acute RV infection also induces significant polyclonal activation of B cells (23). We recently observed that RV infection in suckling mice speeds up the accumulation of IgA ϩ PC in the intestinal LP when compared with noninfected controls.…”

Functional Maturation of the Human Antibody Response to Rotavirus

“…Recently, studies have shown that VP6 interacts with a large fraction of naive B cells from both adults and neonates (7). RV infection causes a T cell-independent expansion of B cells that are responsible for early secretion of anti-RV IgM and activation of APCs for intestinal IgA production (8,9). Although there have been insights into the mechanisms of primary immunity and protection against RV, specific correlates of immunity are lacking.…”