Differentiation of CD4 + T cells into either follicular helper T (T FH ) or type 1 helper T (T H 1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here, we analyzed the spatiotemporal dynamics of CD4 + T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response, but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced the production of the cytokine IL-6 and drove T FH cell polarization, while late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into T H 1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4 + T cell differentiation, and might instruct vaccine design strategies.
LCMV evades B cell responses by recruiting inflammatory monocytes to draining lymph nodes. See related Research Articles by Fallet et al. and Moseman et al. and a Focus by Laidlaw et al.
Immune protection against viral infections relies on the generation of efficient B cell responses and neutralizing antibody (nAb) production. In order to reach full activation, B cells undergo several activation checkpoints in lymph nodes (LN) draining infections sites. In particular, crosstalk between antigen-specific B cells and T follicular helper (Tfh) cells is key to the formation of germinal centers and to the production of high affinity nAbs. However, some viruses (such as lymphocytic choriomeningitis virus [LCMV] in mice, and hepatitis B and C in humans) fail to induce early, potent nAb responses, and can establish persistent infections. We asked whether the lack of nAbs upon LCMV infection reflects a defect in T cell help to B cells. To address this question, we sought to analyze the generation and activation of Tfh cells in the context of LCMV infection as compared to VSV infection, a benchmark for effective nAb responses. Preliminary data show a striking compartmentalization of CD4 T helper responses. In particular, the vast majority of VSV-specific CD4+ T cells differentiated into Tfh and migrated to B cell follicles as early as three days after infection. By contrast, LCMV infection resulted in almost exclusive Th1 differentiation, with little or no Tfh induction. Interestingly, this was independent of the affinity of the TCR for the antigen, since the same LCMV glycoprotein antigen induced Tfh cell differentiation when expressed on a VSV backbone. We are currently utilizing intravital microscopy and gene-expression profile analyses to pinpoint the mechanisms underlying this reduced Tfh differentiation in the context of LCMV infection. Elucidating these mechanisms could pave the way to more efficient vaccination strategies.
Antibodies are critical for protection against viral infections. However, several viruses, such as lymphocytic choriomeningitis virus (LCMV), avoid the induction of early protective antibody responses by poorly understood mechanisms. We analyzed the spatiotemporal dynamics of B cell activation to show that, upon subcutaneous infection, LCMV-specific B cells readily relocate to the interfollicular and T cell areas of draining lymph nodes, where they extensively interact with CD11b+Ly6Chi inflammatory monocytes. These myeloid cells were recruited to lymph nodes draining LCMV infection sites in a type I interferon– and CCR2-dependent fashion, and they suppressed antiviral B cell responses by virtue of their ability to produce nitric oxide. Depletion of inflammatory monocytes, inhibition of their lymph node recruitment, or impairment of their nitric oxide–producing ability enhanced LCMV-specific B cell survival and led to robust neutralizing antibody production. Our results identify inflammatory monocytes as critical gatekeepers that restrain antiviral B cell responses and suggest that certain viruses take advantage of these cells to prolong their persistence within the host.
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