Paracrine costimulation of IFN-? signaling by integrins modulates CD8 T cell differentiation.

ABSTRACT: The cytokine IFN-? is a critical regulator of immune system development and function. Almost all leukocytes express the receptor for IFN-?, yet each cell type elicits a different response to this cytokine. Cell type-specific effects of IFN-? make it difficult to predict the outcomes of the systemic IFN-? blockade and limit its clinical application, despite many years of research. To better understand the cell-cell interactions and cofactors that specify IFN-? functions, we focused on the function of IFN-? on CD8 T cell differentiation. We demonstrated that during bacterial infection, IFN-? is a dominant paracrine trigger that skews CD8 T cell differentiation toward memory. This skewing is preferentially driven by contact-dependent T cell-T cell (T-T) interactions and the localized IFN-? secretion among activated CD8 T cells in a unique splenic microenvironment, and is less sensitive to concurrent IFN-? production by other immune cell populations such as natural killer (NK) cells. Modulation of CD8 T cell differentiation by IFN-? relies on a nonconventional IFN-? outcome that occurs specifically within 24 hours following infection. This is driven by IFN-? costimulation by integrins at T-T synapses, and leads to synergistic phosphorylation of the proximal STAT1 molecule and accelerated IL-2 receptor down-regulation. This study provides evidence of the importance of context-dependent cytokine signaling and gives another example of how cell clusters and the microenvironment drive unique biology.

SUBMITTER: Krummel MF 

PROVIDER: S-EPMC6233119 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature