Upon antigen encounter, T cells become activated, proliferate and differentiate into effector or memory population. Cytokines play a fundamental role in these processes. For example, IFN receptor deficient CD8 T cells do not survive after viral infection. It is thought that type I IFN signaling in T cells imprint survival and effector differentiation quality.
However, two new studies published in Immunity, provided an alternative and surprising explanation for the beneficial effect of type I IFN signaling in T cells. I found the results of these studies to be of sufficient significance to qualify for my review.
One paper has two two co-first authors, Heifeng C. Xu and Melanie Grusdat (1).
In this paper, first set of experiments showed that while in vitro wild-type (WT) and IFN-alpha receptor deficient CD8 T cells behave the same way, in vivo IFN-alpha receptor deficient CD8 T cells (unlike WT CD8 T cells) quickly disappear upon transfer into virus infected host. The same effect was seen with IFN-alpha receptor deficient CD4 T cells (smarta T cells).
Interestingly, adoptive transfer of IFN-alpha receptor deficient CD8 T cells into virus infected host, depleted of NK cells, restored IFN-alpha receptor deficient T cells numbers. The similar effect was seen in virus infected hosts genetically deficient of NK cells (Nfil-deficient mice). These results indicated that NK cells may specifically target activated IFN-alpha receptor deficient T cells for elimination.
In vitro experiment showed that type I IFN signaling induces MHC class I and non-classical MHC Ib (Qa-1b) molecules on the surface of T cells. These molecules were known to inhibit NK cell activity.
Accordingly, in vitro NK cells selectively eliminated IFN-alpha receptor deficient CD8 T cells compared WT CD8 T cells via perforin-mediated pathway. Finally, adoptive transfer of IFN-alpha receptor deficient CD8 T cells into virus infected perforin-deficient hosts restored IFN-alpha receptor deficient T cells numbers and no further increase was detected after NK cell depletion.
In sum, these results indicate that signaling through IFN-alpha receptor in T cells is necessary to prevent early elimination of T cells by primed NK cells after virus infection.
Second paper is from Oxenius lab. The first author is Josh Crouse. It is more detailed study but with the same conclusion (2).
This second group also observed that NK cell depletion with anti-NK1.1 or anti-Asialo GM1 antibody restored expansion of adoptively transferred IFN-alpha receptor deficient T cells (both LCMV specific P14 CD8 T cells and smarta CD4 T cells). Interestingly, only activated but not naïve T cells became sensitive to NK cells. This group also found that adoptive transfer of IFN-alpha receptor deficient P14 CD8 T cells or smarta CD4 T cells into LCMV virus infected perforin-deficient hosts restored IFN-alpha receptor deficient P14 CD8 and smarta CD4 T cells numbers and no further increase was detected after NK cell depletion. Finally, the authors found that NK cells preferentially killed IFN-alpha receptor deficient T cells in vivo and in vitro through NCR1-mediated pathway.
In summary, these two studies showed that during acute viral infection, antigen activated T cells become sensitized to NK cell killing in absence of type I IFN signaling. Mechanistically, in absence of IFN signaling in T cells, T cells upregulate activating NCR1 ligand. Since without type I IFN signaling, inhibitory ligands like MHC class I, are not upregulated, this leads to T cell sensitization to NK cell killing via perforin.
In my view, one important discussion missing from both studies is the role of NK cells or CD8 T cells in acute LCMV infection. Can LCMV infect type I IFN receptor deficient T cells? Why are NK cells targeting T cells at such a early stage of infection (day 3-7)? Is NK cell depletion beneficial for the virus (LCMV)-infected hosts?