Out-of-Sequence Signal 3 as a Mechanism for Virus-Induced Immune Suppression of CD8 T Cell Responses

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. © 2014 urban,welsh.