Collagen fiber structure guides 3D motility of cytotoxic T lymphocytes

Hawley C. Pruitt, Daniel Lewis, Mark Ciccaglione, Sydney Connor, Quinton Smith, John W. Hickey, Jonathan P. Schneck, Sharon Gerecht

Research output: Contribution to journalArticlepeer-review

Abstract

Lymphocyte motility is governed by a complex array of mechanisms, and highly dependent on external microenvironmental cues. Tertiary lymphoid sites in particular have unique physical structure such as collagen fiber alignment, due to matrix deposition and remodeling. Three dimensional studies of human lymphocytes in such environments are lacking. We hypothesized that aligned collagenous environment modulates CD8+ T cells motility. We encapsulated activated CD8+ T cells in collagen hydrogels of distinct fiber alignment, a characteristic of tumor microenvironments. We found that human CD8+ T cells move faster and more persistently in aligned collagen fibers compared with nonaligned collagen fibers. Moreover, CD8+ T cells move along the axis of collagen alignment. We showed that myosin light chain kinase (MLCK) inhibition could nullify the effect of aligned collagen on CD8+ T cell motility patterns by decreasing T cell turning in unaligned collagen fiber gels. Finally, as an example of a tertiary lymphoid site, we found that xenograft prostate tumors exhibit highly aligned collagen fibers. We observed CD8+ T cells alongside aligned collagen fibers, and found that they are mostly concentrated in the periphery of tumors. Overall, using an in vitro controlled hydrogel system, we show that collagen fiber organization modulates CD8+ T cells movement via MLCK activation thus providing basis for future studies into relevant therapeutics.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalMatrix Biology
Volume85-86
DOIs
StatePublished - Jan 2020

Keywords

  • Collagen
  • Fiber alignment
  • Myosin light chain kinase
  • T cells

ASJC Scopus subject areas

  • Molecular Biology

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