CXCL10+ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter
Hen Prizant,
Nilesh Patil,
Seble Negatu,
Noor Bala,
Alexander McGurk,
Scott A. Leddon,
Angela Hughson,
Tristan D. McRae,
Yu-Rong Gao,
Alexandra M. Livingstone,
Joanna R. Groom,
Andrew D. Luster,
Deborah J. Fowell
Affiliations
Hen Prizant
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
Nilesh Patil
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
Seble Negatu
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
Noor Bala
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA
Alexander McGurk
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA
Scott A. Leddon
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA
Angela Hughson
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
Tristan D. McRae
Department of Neuroscience and Multiphoton and Analytical Imaging Center, University of Rochester Medical Center, Rochester, NY, USA
Yu-Rong Gao
Department of Neuroscience and Multiphoton and Analytical Imaging Center, University of Rochester Medical Center, Rochester, NY, USA
Alexandra M. Livingstone
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
Joanna R. Groom
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
Andrew D. Luster
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Deborah J. Fowell
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA; Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA; Corresponding author
Summary: Correct positioning of T cells within infected tissues is critical for T cell activation and pathogen control. Upon tissue entry, effector T cells must efficiently locate antigen-presenting cells (APC) for peripheral activation. We reveal that tissue entry and initial peripheral activation of Th1 effector T cells are tightly linked to perivascular positioning of chemokine-expressing APCs. Dermal inflammation induces tissue-wide de novo generation of discrete perivascular CXCL10+ cell clusters, enriched for CD11c+MHC-II+ monocyte-derived dendritic cells. These chemokine clusters are “hotspots” for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolongs T-APC interactions and boosts function. Both the frequency and range of these clusters are enhanced via a T helper 1 (Th1)-intrinsic, interferon-gamma (IFNγ)-dependent positive-feedback loop. Thus, the perivascular CXCL10+ clusters act as initial peripheral activation niches, optimizing controlled activation broadly throughout the tissue by coupling Th1 tissue entry with enhanced opportunities for Th1-APC encounter.
