Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Several reports have shown an anti proliferative effect o

    2022-01-20


    Several reports have shown an anti-proliferative effect of type I IFNs michele fuortes on CD4+ T michele fuortes activated in vitro either upon anti-CD3 antibody treatment [28,29] or upon cognate antigen stimulation [29]. However, the in vivo setting is a lot more complex, since the final outcome is the net effect of type I IFNs being released by different cell types, with different kinetics and acting on different targets. For instance, it was shown that type I IFN signaling in CD4+ T cells is important for clonal expansion upon acute LCMV infection [29]. When LCMV-specific CD4+ T cells lacking the ability to sense type I IFN were transferred into LCMV-infected mice, CD4+ T cells underwent the initial activation steps (upregulation of the activation markers CD25 and CD69 and early proliferation) but accumulated at a much lower level than their WT counterparts at the peak of the immune response. Interestingly, this was observed upon LCMV but not upon Listeria Monocytogenes (LM) infection [29]; whether this is due to differences in type I IFN production upon the two infections remains to be determined. Another study went further to show that LCMV-specific CD4+ T cells lacking type I IFN receptor could accumulate at levels comparable to their WT counterparts if NK cells were depleted during LCMV infection, suggesting that type I IFN signaling can protect antiviral CD4+ T cells from NK cell-mediated killing, similarly to what has been reported for CD8+ T cells [30,31]. The mechanisms behind this observation seem to involve a type I IFN-mediated upregulation of selected inhibitory NK cell receptor ligands and/or downregulation of natural cytotoxicity triggering receptor 1 (NCR1) ligands on CD4+ (and CD8+) T cells [30,31]. Overall, the abovementioned studies strongly suggest that CD4+ T cell-intrinsic type I IFN signaling is required for survival of primed antiviral CD4+ T cells, especially in the context of acute LCMV infection (Fig. 1). Interestingly, however, when type I IFN signaling was inhibited on all cell types by virtue of an IFNAR-blocking antibody, LCMV-specific CD4+ T cell frequencies during acute LCMV infection were not affected [32]. This unexpected result could be explained either by an incomplete IFNAR blocking by the antibody, or by the pleiotropic and sometimes opposite effects that type I IFNs play on different cellular targets during infection. For example, type I IFNs promote activation and effector function of NK cells upon viral infection [33,34], support DC maturation [35,36] and inhibit T regulatory cell-mediated suppression of antigen-specific CD4+ T cells [37,38] (Fig. 1).
    The above-mentioned studies pretty much converge on the idea that type I IFN signaling (whether CD4+ T cell-intrinsic or -extrinsic) supports rather than interferes with antiviral CD4+ T cell accumulation during acute infection. The picture is quite different, however, if we look at chronic viral infections, where viral persistence induces prolonged expression of type I IFNs [[39], [40], [41]]. Two studies showed that blockade of type I IFN signaling during chronic LCMV infection led to a stronger CD4+ T cell response that was responsible for faster viral clearance [32,42]. Sustained type I IFN production during chronic LCMV infection induced expression of PD-L1 and IL-10 by immunoregulatory DCs, thereby contributing to an immunosuppressive environment (Fig. 1). Since in the abovementioned studies type I IFN signaling was blocked ubiquitously, however, it is impossible to definitively ascertain the target cell(s) responsible for the observed net effect. Besides DCs, there are likely additional cellular targets for type I IFN during chronic LCMV infection, potentially with opposing effects. For instance, selective deletion of type I IFN receptors in Tregs during chronic LCMV infection led to higher viral titers and increased frequency of PD-1-expressing exhausted T cells – although the effect on CD4+ T cells was less pronounced than that on CD8+ T cells [38]. It should be noted that in this latter setting, DCs could still sense type I IFNs, acquire a suppressive phenotype, and promote exhaustion of antiviral CD4+ T cells.