TY - JOUR
T1 - Collagen fiber structure guides 3D motility of cytotoxic T lymphocytes
AU - Pruitt, Hawley C.
AU - Lewis, Daniel
AU - Ciccaglione, Mark
AU - Connor, Sydney
AU - Smith, Quinton
AU - Hickey, John W.
AU - Schneck, Jonathan P.
AU - Gerecht, Sharon
N1 - Funding Information:
This work was funded by the Johns Hopkins Physical Science-Oncology Center 5U54CA210173-03 and the Patrick C. Walsh Prostate Cancer Research Fund and the Johns Hopkins Prostate Cancer SPORE P30CA006973 (to SG) and fellowship from the Nanotechnology for Cancer Research Training Grant 5T32CA153952-09 (to HCP). The authors acknowledge services provided by the Johns Hopkins University Oncology Tissue Services core Sydney Kimmel Cancer Center (P30 CA006973) as well as the Johns Hopkins University Integrated Imaging Center.
Funding Information:
This work was funded by the Johns Hopkins Physical Science-Oncology Center 5U54CA210173-03 and the Patrick C. Walsh Prostate Cancer Research Fund and the Johns Hopkins Prostate Cancer SPORE P30CA006973 (to SG) and fellowship from the Nanotechnology for Cancer Research Training Grant 5T32CA153952-09 (to HCP). The authors acknowledge services provided by the Johns Hopkins University Oncology Tissue Services core Sydney Kimmel Cancer Center (P30 CA006973) as well as the Johns Hopkins University Integrated Imaging Center.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
KW - Collagen
KW - Fiber alignment
KW - Myosin light chain kinase
KW - T cells
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U2 - 10.1016/j.matbio.2019.02.003
DO - 10.1016/j.matbio.2019.02.003
M3 - Article
C2 - 30776427
AN - SCOPUS:85061819378
VL - 85-86
SP - 147
EP - 159
JO - Collagen and Related Research
JF - Collagen and Related Research
SN - 0945-053X
ER -