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

Abstract

SUMMARYCorrect 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, 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.

Spatially organized multicellular immune hubs in human colorectal cancer

“…A third study showed that vaccination of mice induced an IFNg/CXCR3-dependent spatial hub of T cells and myeloid cells expressing CXCL10. This hub formed around the vasculature and facilitated entry of circulating T cells into the tissue (Prizant et al, 2021), providing a platform for frequent encounters of T cells with other cells to coordinate immune responses.…”

Multicellular immune hubs and their organization in MMRd and MMRp colorectal cancer

“…A third study showed that vaccination of mice induced an IFNG/CXCR3-dependent spatial hub of T cells and myeloid cells expressing CXCL10. This hub formed around the vasculature and facilitated entry of circulating T cells into the tissue 66 , thus providing a platform for frequent encounters of T cells with other cells to coordinate immune responses.…”

T cell activation niches—Optimizing T cell effector function in inflamed and infected tissues*

“…While the recent study of the adventitial cuff suggests this pre‐positioned innate activation niche can also serve as a site for subsequent effector T cell activation, 103 it remains unclear whether the induced clustering of effector T cells with APCs seen in many inflamed tissues (Table 1) arises at predetermined locations within the tissue parenchyma. A growing body of evidence points to the de novo assembly of microanatomical activation hubs located perivascularly that are induced following immune challenge and that underpin T cell immunity within inflamed tissues 4,5,7,8,86,117‐119 …”

“…The specific immune cells recruited to this niche will likely differ depending on the tissue and the type of pathogen; however, common themes are emerging. The induction of innate signals, such as type 1 interferons, initiate the activation and recruitment of myeloid subsets to the perivascular space, where local niche‐specific chemokine production and antigen presentation optimizes encounter with incoming effector T cells 4,5 . It is not yet known if the induced perivascular niche arises from any strategic positioning that might optimize enrichment of antigen, as seen in the SCS of the LN or the adventitial cuff.…”

“…Emerging studies in a variety of tissues, including the skin, brain, liver, and lung, as well as tumors, suggest that T cell activation niches can be induced in inflamed tissues under the control of localized chemokine signals emanating from tissue resident or recruited innate immune cells. These activation niches are context and tissue specific but serve the same purpose, to amplify the recruitment (and possible retention) of effector T cells to microanatomical sites enriched for antigen presentation and activation 4‐8 . Positional cues that facilitate niche development and function include chemokines and other chemotactic or chemo‐repulsive factors, adhesive signals from integrins and their ligands, and antigen and costimulatory molecules (Figure 1).…”