Intestinal Batf3-dependent dendritic cells are required for optimal antiviral T-cell responses in adult and neonatal mice

Abstract

Although we know a great deal about which types of dendritic cells (DCs) promote T-cell priming in the periphery, less is known about which DC subset(s) provoke antiviral responses within the gut. Here we report that conventional Zbtb46-dependent DCs were critically required for antiviral CD8 T-cell responses against rotavirus (RV), the major cause of childhood gastroenteritis worldwide. Furthermore, we found that in adult mice, Batf3-dependent DCs were required for generating optimal RV-specific CD8 T-cell responses. However, in contrast to mice that lack Zbtb46-dependent DCs, a significant amount of interferon gamma-producing RV-specific CD8 T cells were still detected in the small intestine of RV-infected adult Batf3 mice, suggesting the existence of compensatory cross-presentation mechanisms in the absence of Batf3-dependent DCs. In contrast to adult mice, we found that Batf3-dependent DCs were absolutely required for generating RV-specific CD8 T-cell responses in neonates. Loss of Batf3-dependent DCs also resulted in a skewed polyclonal CD4 T-cell response in both adult and neonatal mice upon RV infection, although local and systemic RV-specific immunoglobulin A production kinetics and titers were unimpaired. Our results provide insights that inform early-life vaccination strategies against RV infection.

NLRC5 deficiency has a moderate impact on immunodominant CD8+ T‐cell responses during rotavirus infection of adult mice

“…Early after RV infection, Peyer's patch (PP) dendritic cells (DCs) upregulate costimulatory molecules such CD80, CD86 and CD40, suggesting a robust activation of intestinal DC post‐RV infection. We have previously shown that intestinal classical DCs are professional antigen‐presenting cells that cross‐present viral antigens to CD8 + T cells upon RV infection . Therefore, we next sought to analyze if DC‐intrinsic NLRC5 regulated MHC‐I expression and impacted CD8 + T‐cell responses.…”

“…In this study, we demonstrated that the RV‐specific CD8 + T‐cell response is moderately decreased in the absence of Nlrc5 in CD11c‐expressing cells. While the CD11c‐cre mouse strain may also delete floxed genes in macrophages and activated T cells as well as B cells (Supplementary figure 2), which can express CD11c, we have previously shown that Batf3 ‐dependent conventional DC (cDC) 1 are required for optimal anti‐RV CD8 + T‐cell response in the SILP . Therefore, we predicted that the absence of Nlrc5 in Batf3 ‐dependent dependent cDC 1 may downregulate MHC‐I expression and the cognate CD8 + T‐cell responses.…”

“…Although macrophages can contribute to CD8 + T-cell priming, DCs are considered the most important and efficient professional antigen-presenting cells in most instances and indeed, we have previously shown that macrophages are not critical for the CD8 + Tcell response in the context of rotavirus infection in adult mice. 29 We also ruled out a role for NLRC5 in T cells; indeed, adoptive transfer of WT and Nlrc5-deficient CD8 + T cells into Rag1 À/À mice treated with NK1.1 blocking antibody (as described 26) showed no difference in the ability of Nlrc5-deficient CD8 + T cells in being primed by WT DCs (data not shown).…”

“…While the CD11c-cre mouse strain may also delete floxed genes in macrophages and activated T cells as well as B cells (Supplementary figure 2), which can express CD11c, we have previously shown that Batf3-dependent conventional DC (cDC) 1 are required for optimal anti-RV CD8 + T-cell response in the SILP. 29 Therefore, we predicted that the absence of Nlrc5 in Batf3-dependent dependent cDC 1 may downregulate MHC-I expression and the cognate CD8 + Tcell responses. Rota et al reported that NLRC5 deficiency in DCs is not sufficient to hinder OT-I T-cell activation.…”

“…We have previously shown that intestinal classical DCs are professional antigen-presenting cells that cross-present viral antigens to CD8 + T cells upon RV infection. 29 Therefore, we next sought to analyze if DC-intrinsic NLRC5 regulated MHC-I expression and impacted CD8 + T-cell responses. We therefore crossed Nlrc5 fl/fl mice with CD11c-Cre mice and generated CD11c-Nlrc5 À/À mice and littermate controls (Nlrc5 fl/fl ).…”