Grassmann and Santosa et al. showed that temporal integration of antigen and inflammatory cytokine signals, not solely signal availability, determined lymphocyte fate. Antigen receptor engagement before IL-12 signaling initiated an adaptive NK cell response during MCMV infection, whereas IL-12 signaling without prior antigen exposure enforced terminal effector differentiation. Antigen priming led to chromatin changes that redirected STAT4 genomic binding away from ETS/RUNX motifs and toward AP-1 binding sites. In CD8+ T cells, AP-1/STAT4 cooperation depended on TCR avidity and signal strength, and determined effector versus memory differentiation.
Contributed by Shishir Pant
ABSTRACT: Lymphocyte differentiation during infection depends on the integration of antigen and cytokine signals, yet how the timing and sequence of these cues program cell fate remains unclear. We found that interleukin-12 (IL-12) plays a context-dependent role in immune memory formation. Without prior antigen-receptor signaling, IL-12 drove cytotoxic lymphocytes toward terminal effector differentiation. In contrast, antigen signaling redirected IL-12-STAT4 activity through cooperation with AP-1 transcription factors to promote memory formation. This stepwise signal integration enabled lymphocytes to acquire memory rather than effector fates. Whereas CD8(+) T cells were protected from premature IL-12 signaling by delayed receptor expression, natural killer (NK) cells, which constitutively express the IL-12 receptor, must engage their antigen receptor before cytokine signaling for efficient adaptive programming. Together, these findings define a framework in which sequential antigen and cytokine signaling coordinates effector versus memory differentiation, ensuring both robust primary responses and selective enrichment of high-avidity memory clones.
Author Info: (1) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: grassmas@mskcc.org. (2) Immunology Program, Memorial Sloan Kettering Ca
Author Info: (1) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: grassmas@mskcc.org. (2) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (3) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (5) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (8) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. (9) Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany. (10) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. (11) Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. (12) Institute for Medical Microbiology, Immunology and Hygiene, TUM School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany; German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany. (13) Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. (14) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: sunj@mskcc.org.
