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

doi:10.1016/j.celrep.2021.109523

CXCL10⁺ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter

Cell Rep. 2021 Aug 10;36(6):109523. doi: 10.1016/j.celrep.2021.109523.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Neuroscience and Multiphoton and Analytical Imaging Center, University of Rochester Medical Center, Rochester, NY, USA.
⁴ Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
⁵ Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ 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. Electronic address: djf273@cornell.edu.

Abstract

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.

Keywords: CD4 T cells; CXCL10; CXCR3; Th1; chemokine; inflammation; intra-vital multiphoton microscopy; moDCs; perivascular; skin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigen-Presenting Cells / metabolism*
Antigens / metabolism
Antigens, CD / metabolism
Cell Aggregation
Chemokine CXCL10 / metabolism*
Ear / pathology
Histocompatibility Antigens Class II / metabolism
Humans
Inflammation / pathology
Interferon-gamma
Lymphocyte Activation / immunology*
Mice
Mice, Transgenic
Receptors, CXCR3 / metabolism
Skin / pathology
Th1 Cells / immunology*

Substances

Antigens
Antigens, CD
Chemokine CXCL10
Histocompatibility Antigens Class II
Receptors, CXCR3
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding