Anti-viral CD8 T cells and the cytokines that they love

Abstract

Viral infections cause an immunological disequilibrium that provokes CD8 T cell responses. These cells play critical roles in purging acute infections, limiting persistent infections, and conferring life-long protective immunity. At every stage of the response anti-viral CD8 T cells are sensitive to signals from cytokines. Initially cytokines operate as immunological warning signs that inform of the presence of an infection, and also influence the developmental choices of the responding cells. Later during the course of the response other sets of cytokines support the survival and maintenance of the differentiated anti-viral CD8 T cells. Although many cytokines promote virus-specific CD8 T cells, other cytokines can suppress their activities and thus favor viral persistence. In this review we discuss how select cytokines act to regulate anti-viral CD8 T cells throughout the response and influence the outcome of viral infections.

Fig. 1

The development of phenotypically and functionally distinct subsets of anti-viral CD8 T cells over time during acute viral infections. As the infection becomes established the small number of available naïve virus-specific CD8 T cells are activated and modify their expression of adhesion molecules, cytokine receptors, and transcription factors. These activated CD8 T cells undergo clonal expansion and differentiate into expanded populations of fully-fledged but short-lived effector T cells and this often overwhelming response operates to purge the virus infection. Distinct populations of effector CD8 T cells also develop which attain a memory precursor phenotype. As the infection is cleared the overall T cell response contracts and the short-lived effector cells are disposed by apoptosis, whereas the memory precursor cells are preferentially maintained and mature into the long-lived anti-viral memory T cell pool. Further phenotypic and functional diversity is observed within the memory T cell population and shifts in these attributes can occur over time.

Fig. 2

Cytokines influence the developmental choices of anti-viral CD8 T cells. Although CD8 T cell responses are triggered by the detection of viral antigens, other factors amplify and guide their development. The presence of several cytokines including type I interferons, IL-12, IL-33, and high levels of IL-2 have been shown to drive the differentiation of short-lived terminally differentiated effector CD8 T cells during the initial stages of the response. The magnitude of the effector response may be lower if these cytokine signals are ablated, but memory T cell development can still occur.

Fig. 3

The differentiation of anti-viral CD8 T cells is corrupted during chronic viral infections. Various factors including high viral loads, the composition of the cytokine milieu, and ineffective CD4 T cell help contribute to the induction of ineffective anti-viral CD8 T cell responses. Under these conditions the responding T cells usually attain a highly activated phenotype and express ensembles of inhibitory receptors as they progressively lose their ability to elaborate key anti-viral effector activities. Unlike their memory counterparts, these exhausted T cells usually require the continued presence of viral antigen for their maintenance and may succumb to deletion over time.

Fig. 4

Antigen-dependent and independent activation of effector and memory virus-specific CD8 T cells. Effector and memory CD8 T cells that develop in response to viral-infections are endowed with the ability to become rapidly activated and deploy effector functions if they re-encounter their cognate viral antigen. This allows virus-specific T cells to swiftly target virus-infected cells, and limit and control the infection. Effector and memory CD8 T cells can also become activated and produce effector cytokines, including IFNγ, if they are exposed to certain cytokine combinations, most notably IL-12 and IL-18. This sensitivity to cytokine activation enables the CD8 T cells to mount bystander responses, which may operate to help control the new infection and mobilize the host immune response.