Abstract
The proinflammatory cytokine IL-12 drives the generation of terminally differentiated KLRG1(+) effector CD8(+) T cells. Using a Toxoplasma vaccination model, we delineate the sequence of events that naïve CD8(+) T cells undergo to become terminal effectors and the differentiation steps controlled by IL-12. We demonstrate that direct IL-12 signaling on CD8(+) T cells is essential for the induction of KLRG1 and IFN-γ, but the subsequent downregulation of CXCR3 is controlled by IL-12 indirectly through the actions of IFN-γ and IFN-γ-inducible chemokines. Differentiation of nascent effectors occurs in an extrafollicular splenic compartment and is driven by late IL-12 production by DCs distinct from the classical CD8α(+) DC. Unexpectedly, we also found extensive proliferation of both KLRG1(-) and KLRG1(+) CD8(+) T cells in the marginal zone and red pulp, which ceases prior to the final KLRG1(Hi) CXCR3(Lo) stage. Our findings highlight the notion of an extrafollicular pathway for effector T cell generation.
Highlights
The activation of naıve CD8+ T cells occurs in the T cell areas of secondary lymphoid organs (Mempel et al, 2004)
These results indicate that the lack of IL-12 signals does not affect the timing or the magnitude of the proliferative response of tgd057-specific CD8+ T cells during T. gondii vaccination
We identify the sequence of events that naıve CD8+ T cells undergo as they differentiate into effector CD8+ T cells in response to infection with the intracellular protozoan pathogen, T. gondii
Summary
The activation of naıve CD8+ T cells occurs in the T cell areas of secondary lymphoid organs (Mempel et al, 2004). CD8+ T cells are thought to undergo rapid clonal expansion and differentiate into IFN-γ-producing effector cytotoxic lymphoid cells (CTLs) through an ‘autopilot’ mechanism (Mercado et al, 2000; Bevan and Fink, 2001; Kaech and Ahmed, 2001; van Stipdonk et al, 2001). Consistent with this paradigm, CD8α+ dendritic cells (DCs), which are resident in the splenic white pulp, are critical for both antigen cross-presentation (den Haan et al, 2000) and production of a key pro-inflammatory cytokine, IL-12 (Reis e Sousa et al, 1997; Mashayekhi et al, 2011). CXCR3-mediated outmigration of T cells into the splenic marginal zone (MZ) (Kurachi et al, 2011) or the peripheral medullary areas of lymph nodes (Groom et al, 2012) enables interactions with
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