title: An extrafollicular pathway for the generation of effector CD8(+) T cells driven by the proinflammatory cytokine, IL-12.
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.
authors.affiliation: Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, United States.
authors.forename: Suhagi
authors.initials: S
authors.lastname: Shah
authors.affiliation: Immunology Programme, Departments of Microbiology and Biological Sciences, National University of Singapore, Singapore, Singapore.
authors.forename: Gijsbert M
authors.initials: GM
authors.lastname: Grotenbreg
authors.affiliation: Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, United States.
authors.forename: Amariliz
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, United States.
authors.forename: George S
authors.initials: GS
authors.lastname: Yap
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007371:Interferon-gamma; D018664:Interleukin-12 / Q000378:metabolism*; D037181:Lectins, C-Type; D008297:Male; D008810:Mice, Inbred C57BL; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology*
chemical_list: C515188:Cxcr3 protein, mouse; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D016052:Protozoan Vaccines; D054367:Receptors, CXCR3; D011971:Receptors, Immunologic; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: CD8 T cells; Toxoplasma; effector cells; extrafollicular; immunology; infectious disease; interleukin-12; microbiology; mouse; myeloid DC