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.
The origin of axoplasmic RNA in the squid giant fiber was investigated after exposure of the giant axon or of the giant fiber lobe to [3H]uridine. The occurrence of a local process of synthesis was indicated by the accumulation of labeled axoplasmic RNA in isolated axons incubated with the radioactive precursor. Similar results were obtained in vivo after injection of [3H]uridine near the stellate nerve at a sizable distance from the ganglion. Exposure of the giant fiber lobe to [3H]uridine under in vivo and in vitro conditions was followed by the appearance of labeled RNA in the axoplasm and in the axonal sheath. While the latter process is attributed to incorporation of precursor by sheath cells, a sizable fraction of the radioactive RNA accumulating in the axoplasmic is likely to originate from neuronal perikarya by a process of axonal transport.
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.
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