| First Author | Krummel MF | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 45 | Pages | 11585-11590 |
| PubMed ID | 30348790 | Mgi Jnum | J:267458 |
| Mgi Id | MGI:6256649 | Doi | 10.1073/pnas.1804556115 |
| Citation | Krummel MF, et al. (2018) Paracrine costimulation of IFN-gamma signaling by integrins modulates CD8 T cell differentiation. Proc Natl Acad Sci U S A 115(45):11585-11590 |
| abstractText | The cytokine IFN-gamma is a critical regulator of immune system development and function. Almost all leukocytes express the receptor for IFN-gamma, yet each cell type elicits a different response to this cytokine. Cell type-specific effects of IFN-gamma make it difficult to predict the outcomes of the systemic IFN-gamma blockade and limit its clinical application, despite many years of research. To better understand the cell-cell interactions and cofactors that specify IFN-gamma functions, we focused on the function of IFN-gamma on CD8 T cell differentiation. We demonstrated that during bacterial infection, IFN-gamma 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-gamma secretion among activated CD8 T cells in a unique splenic microenvironment, and is less sensitive to concurrent IFN-gamma production by other immune cell populations such as natural killer (NK) cells. Modulation of CD8 T cell differentiation by IFN-gamma relies on a nonconventional IFN-gamma outcome that occurs specifically within 24 hours following infection. This is driven by IFN-gamma 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. |
