IL-12-programmed long-term CD8+ T cell responses require STAT4.
Immunological adjuvants activate innate immune cells for Ag presentation and elicitation of cytokines like IL-12 that promote T cell expansion and effector differentiation. An important but elusive aim for most immunization strategies is to produce memory T cells that provide durable immunity. Recent evidence demonstrates that the context of Ag presentation instructionally programs T cells for short- and long-term responses. However, the role and mechanisms by which cytokines like IL-12 condition CD8 T cells for long-term responses remain relatively uncharacterized. In this study, we show that brief exposure (20 h) of naive TCR-transgenic CD8 cells to IL-12 during Ag stimulation leads to transient phosphorylation of STAT4 for robust effector differentiation. Moreover, the IL-12-induced STAT4 engenders greater clonal expansion of the Ag-activated CD8 cells by regulating the expression of the transcriptional factor Bcl3- and Bcl2-related genes that promote survival of Ag-activated CD8 cells. Remarkably, the IL-12-conditioned CD8 T cells demonstrate increased sensitivity to IL-7 and IL-15, whereby they are rendered "fit" for homeostatic self-renewal as well as augmented CD4-dependent recall responses that are effective at controlling Salmonella infection in vivo. This information provides new insights into mechanisms by which IL-12 conditions CD8 T cells for long-term immunity, which is likely to benefit development of new strategies for the use of IL-12 in infectious diseases and cancer.
Li
Qingsheng
Q
Department of Immunology, Roswell Park Cancer Institute, 322 Cancer Cell Center, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Eppolito
Cheryl
C
Odunsi
Kunle
K
Shrikant
Protul A
PA
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D007156:Immunologic Memory; D007375:Interleukin-1 / Q000276:immunology*; D019409:Interleukin-15 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D007375:Interleukin-1; D019409:Interleukin-15; D015851:Interleukin-7; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D014157:Transcription Factors; C052617:Bcl2 protein, mouse