Virus infections are known to induce a transient state of immune suppression often associated with an inhibition of T cell proliferation in response to mitogen or cognate-antigen stimulation. Recently, virus-induced immune suppression has been linked to responses to type 1 interferon (IFN), a signal 3 cytokine that normally can augment the proliferation and differentiation of T cells exposed to antigen (signal 1) and co-stimulation (signal 2). However, pre-exposure of CD8 T cells to IFN-inducers such as viruses or poly(I∶C) prior to antigen signaling is inhibitory, indicating that the timing of IFN exposure is of essence. We show here that CD8 T cells pretreated with poly(I∶C) down-regulated the IFN receptor, up-regulated suppressor of cytokine signaling 1 (SOCS1), and were refractory to IFNβ-induced signal transducers and activators of transcription (STAT) phosphorylation. When exposed to a viral infection, these CD8 T cells behaved more like 2-signal than 3-signal T cells, showing defects in short lived effector cell differentiation, reduced effector function, delayed cell division, and reduced levels of survival proteins. This suggests that IFN-pretreated CD8 T cells are unable to receive the positive effects that type 1 IFN provides as a signal 3 cytokine when delivered later in the signaling process. This desensitization mechanism may partially explain why vaccines function poorly in virus-infected individuals.
Vaccines are used to protect individuals against infection with a number of different pathogens and depend on the formation of antigen specific memory cells. The efficacy of vaccines can be affected by a number of different factors. It has been known for some time now that suppression of the immune system occurs during acute viral infections. Thus, receiving a vaccine during an acute illness may reduce the efficacy of the vaccine administered. We have identified a common mechanism of immune suppression that may occur with many different pathogens that induce a particular inflammatory response. Any pathogen that induces type 1 interferon could potentially suppress the immune response to a subsequent pathological insult. The mechanism of immune suppression identified here was not having a direct negative effect on lymphocytes, but rather was inhibiting the cells ability to receive positive signals that influence their differentiation, expansion and memory formation. This desensitization mechanism may partially explain why vaccines function poorly in virus-infected individuals.