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

Prizant, H.; Patil, N.; Negatu, S.; McGurk, A.; Leddon, S. A.; Hughson, A.; McRae, T. D.; Gao, Y.; Livingstone, A. M.; Groom, J. R.; Luster, A. D.; Fowell, D. J.

doi:10.1101/2020.10.04.324525

bioRxiv · 10.1101/2020.10.04.324525

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

Prizant, H.·Patil, N.·Negatu, S.·McGurk, A.·Leddon, S. A.·Hughson, A.·McRae, T. D.·Gao, Y.·Livingstone, A. M.·Groom, J. R.·Luster, A. D.·Fowell, D. J.

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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 induced tissue-wide de novo generation of discrete perivascular CXCL10+ cell clusters, enriched for CD11c+MHC-II+ monocyte-derived dendritic cells. These chemokine clusters were hot spots for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolonged T-APC interactions and boosted function. Both the frequency and range of these clusters were enhanced via a Th1-intrinsic, IFN{gamma}-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.

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Prizant, H., Patil, N., Negatu, S., McGurk, A., Leddon, S. A., Hughson, A., McRae, T. D., Gao, Y., Livingstone, A. M., Groom, J. R., Luster, A. D., Fowell, D. J.. 2020-10-04. CXCL10+ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter. https://doi.org/10.1101/2020.10.04.324525

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