Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues.
Activated T cells must mediate effector responses sufficiently to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4(+) T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen-presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs T cell recruitment, transient activation, and rapid desensitization to allow the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host.
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Tetsuya
T
Honda
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Jackson G
JG
Egen
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Tim
T
Lämmermann
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Wolfgang
W
Kastenmüller
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.|Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Parizad
P
Torabi-Parizi
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Ronald N
RN
Germain
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D002465:Cell Movement; D025461:Feedback, Physiological; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D011948:Receptors, Antigen, T-Cell