Dataset Information

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

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.

SUBMITTER: Prizant H

PROVIDER: S-EPMC9218982 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

CXCL10<sup>+</sup> peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter.

Prizant Hen H Patil Nilesh N Negatu Seble S Bala Noor N McGurk Alexander A Leddon Scott A SA Hughson Angela A McRae Tristan D TD Gao Yu-Rong YR Livingstone Alexandra M AM Groom Joanna R JR Luster Andrew D AD Fowell Deborah J DJ

Cell reports 20210801 6

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<sup>+</sup> cell ...[more]

PMID: 34380032

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Project description:Expression of programmed cell death-1 receptor (PD-1) has traditionally been linked to T-cell exhaustion, as signaling via PD-1 dampens the functionality of T-cells upon repetitive antigen exposures during chronic infections. However, resent findings pointing to the involvement of PD-1 both in T-cell survival and in restraining immunopathology, challenge the concept of PD-1 solely as marker for T-cell exhaustion. Tissue resident memory T cells (Trms) hold unique effector qualities, but within a delicate organ like the CNS, these protective abilities could potentially be harmful. In contrast to their counterparts in many other tissues, brain derived CD8+ Trms have been found to uniformly and chronically express PD-1. In this study we utilized a recently established model system for generating CNS Trms in order to improve our understanding regarding the role of PD-1 expression by Trms inside the CNS. By intracerebral (i.c.) inoculation with a non-replicating adeno-viral vector, we induced a PD-1hi CD8+ T cell memory population within the CNS. We found that PD-1 expression lowered the severity of clinical disease associated with the i.c. inoculation. Furthermore, high levels of PD-L1 expression were found on the infiltrating monocytes and macrophages as well as on the resident microglia, oligodendrocytes and astrocytes during the acute phase of the response. Additionally, we showed that the intensity of PD-1 expression correlates with local antigen encounter and found that PD-1 expression was associated with decreased CD8+ T cell memory formation in the CNS despite an increased number of infiltrating CD8+ T cells. Most importantly, our experiments revealed that despite expression of PD-1 and several additional markers linked to T-cell exhaustion, Tim-3, Lag-3 and CD39, the cells did not show signs of limited effector capacity. Collectively, these results endorse the increasing amount of evidence pointing to an immune-modifying role for PD-1 expression within the CNS, a mechanism we found to correlate with local antigen exposure.

Dataset Information

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

Publications

CXCL10<sup>+</sup> peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter.

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Dataset Information

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

Publications

CXCL10<sup>+</sup> peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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