IntroductionThe incubation period of many viral infections is characterized by a transient reduction of peripheral blood lymphocyte counts, a phenomenon called lymphopenia. In mice infected with virus or treated with TLR ligands, lymphopenia in blood and lymph was related to IFN-␣/␤. 1,2 In line with this, lymphopenia is reported as a side effect of IFN-␣/␤ therapy for multiple sclerosis and chronic hepatitis. 3,4 Similarly, treatment with IFN-␥, IL-2, TNF-␣, 5 and IL-12 6 and chemical compounds including FTY720 7 were reported to cause a reduction of leukocyte subsets in patients' blood.Interferons are classified into 2 distinct families, IFN-␣/␤ (or type I IFN) and IFN-␥ (or type II IFN). IFN-␣/␤ binds to the heterodimeric type I interferon receptor (IFNAR), composed of an ␣-chain, which is essential for signaling, and a ␤-chain. In addition to antiviral activity, [8][9][10] IFN-␣/␤ can have an impact on lymphocyte proliferation, 11 apoptosis, 12 and expression of cytokines and cytokine receptors, [13][14][15][16] causing immune modulation in vivo. [17][18][19] IFN-␣/␤ exerts direct and indirect effects on lymphocytes. A critical role of IFN-␣/␤ in CD8 ϩ T-cell cross-priming has been shown. 20 This could recently be identified as a direct effect on CD8 ϩ T cells, promoting clonal expansion and memory T-cell formation by increased cell survival. 21 Furthermore, IFN-␣/␤ can directly stimulate naive T cells, 22,23 promote plasma cell differentiation, and enhance B-cell responses. [24][25][26][27][28] Many indirect effects of IFN-␣/␤ on lymphocytes are presumably mediated by the activation of antigen-presenting cells, 26,29-31 which in turn secrete various cytokines, such as IL-15, that can act on lymphocytes. 16 Apart from activating B and T cells, IFN-␣/␤ can influence lymphocyte homeostasis by suppressing hematopoiesis 32 or enhancing the output of lymphocyte precursors. 33 Lymphocytes continuously home to secondary lymphoid organs (SLOs) and recirculate through lymph and blood. Homing relies on a cascade of events guided by selectins, integrins, chemokine receptors, and sphingosine 1-phosphate receptor 1 (S1P 1 ). [34][35][36] The expression of homing receptors on lymphocytes and endothelium is stringently controlled and correlates with the cellular differentiation state. [37][38][39][40][41] It is conceivable that IFN-␣/␤ affects circulation and homing of lymphocytes because it can induce chemokines and modulate adhesion molecules in human T-cell lines 42 and endothelial cells. 43 Stimulation with the TLR7 ligand R-848 causes pronounced lymphopenia and enhances rolling and sticking of lymphocytes, concomitant with increased expression of several adhesion molecules on endothelia. 44 Furthermore, treatment with FTY720 reduces S1P 1 expression and leads to lymphopenia and lymphocyte sequestration in lymphoid organs. 7,45,46 In essence, however, the mechanism of lymphopenia and the cellular targets of cytokines and other factors remain elusive.In the present study, we have analyzed the role of IFN-␣/␤ in lymphope...

Type I IFN (IFN-αβ) is induced rapidly by infection and plays a key role in innate antiviral defense. IFN-αβ also exerts stimulatory effects on the adaptive immune system and has been shown to enhance Ab and T cell responses. We have investigated the importance of B and T cells as direct targets of IFN-αβ during IFN-α-mediated augmentation of the Ab response against a soluble protein Ag. Strikingly, the ability of IFN-α to stimulate the Ab response and induce isotype switching was markedly reduced in mice in which B cells were selectively deficient for the IFN-αβR. Moreover, IFN-α-mediated enhancement of the Ab response was also greatly impaired in mice in which T cells were selectively IFN-αβR-deficient. These results indicate that IFN-αβR signaling in both B and T cells plays an important role in the stimulation of Ab responses by IFN-αβ.

Type I IFN (IFN-αβ), which is produced rapidly in response to infection, plays a key role in innate immunity and also acts as a stimulus for the adaptive immune response. We have investigated how IFN-αβ induces cross-priming, comparing CD8+ T cell responses generated against soluble protein Ags in the presence or absence of IFN-αβ. Injection of IFN-α was found to prolong the proliferation and expansion of Ag-specific CD8+ T cells, which was associated with marked up-regulation of IL-2 and IL-15 receptors on Ag-specific cells and expression of IL-15 in the draining lymph node. Surprisingly, neither IL-2 nor IL-15 was required for IFN-α-induced cross-priming. Conversely, expression of the IFN-αβR by T cells was shown to be necessary for effective stimulation of the response by IFN-α. The finding that T cells represent direct targets of IFN-αβ-mediated stimulation reveals an additional mechanism by which the innate response to infection promotes adaptive immunity.

BackgroundFeline Panleukopenia (FPL) is a serious disease of cats that can be prevented by vaccination. Kittens are routinely vaccinated repeatedly during their first months of life. By this time maternally derived antibodies (MDA) can interfere with vaccination and inhibit the development of active immunity. The efficacy of primary vaccination under field conditions was questioned by frequent reports to the Paul-Ehrlich-Institut on outbreaks of FPL in vaccinated breeding catteries. We therefore initiated a field study to investigate the development of immunity in kittens during primary vaccination against FPL.64 kittens from 16 litters were vaccinated against FPL at the age of 8, 12 and 16 weeks using three commercial polyvalent vaccines. Blood samples were taken before each vaccination and at the age of 20 weeks. Sera were tested for antibodies against Feline Panleukopenia Virus (FPV) by hemagglutination inhibition test and serum neutralisation assay in two independent diagnostic laboratories.ResultsThere was a good correlation between the results obtained in different laboratories and with different methods. Despite triple vaccination 36.7% of the kittens did not seroconvert. Even very low titres of MDA apparently inhibited the development of active immunity. The majority of kittens displayed significant titres of MDA at 8 and 12 weeks of age; in some animals MDA were still detected at 20 weeks of age. Interestingly, the vaccines tested differed significantly in their ability to overcome low levels of maternal immunity.ConclusionsIn the given situation it is recommended to quantify antibodies against FPV in the serum of the queen or kittens before primary vaccination of kittens. The beginning of primary vaccination should be delayed until MDA titres have declined. Unprotected kittens that have been identified serologically should be revaccinated.

Vesicular stomatitis virus (VSV) infection rapidly induces IFN-αβ that confers initial survival, whereas long-term protection is mediated by neutralizing IgG responses. Because coadministration of IFN-αβ can enhance Ab responses against soluble Ags, we addressed whether virus-induced IFN-αβ also had an impact on the induction of neutralizing Ab responses. To this end, we generated apathogenic retrovirus-like particles (VLP) displaying the VSV gp (VLP-VSV). Reminiscent of live VSV, VLP-VSV induced VSV-neutralizing IgM responses that switched to IgG in a T help-dependent manner. In type I IFN receptor-deficient (IFNAR−/−) mice, VLP-VSV injection elicited neutralizing IgM, whereas the IgG switch was absent. The lack of subclass switch was associated with a reduced germinal center reaction. Conditional knockout mice with a lymphocyte-specific IFNAR ablation showed normal Ab responses against VLP-VSV, as well as against live VSV. Thus, IFNAR triggering critically promoted the T help-dependent subclass switch of virus-neutralizing Ab responses against VLP-VSV. Interestingly, in the context of VLP-VSV as well as VSV immunization, IFNAR triggering of B lymphocytes did not play a critical role.

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