Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites

T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2019-08, Vol.51 (2), p.298-309.e6
Main Authors: Gaylo-Moynihan, Alison, Prizant, Hen, Popović, Milan, Fernandes, Ninoshka R.J., Anderson, Christopher S., Chiou, Kevin K., Bell, Hannah, Schrock, Dillon C., Schumacher, Justin, Capece, Tara, Walling, Brandon L., Topham, David J., Miller, Jim, Smrcka, Alan V., Kim, Minsoo, Hughson, Angela, Fowell, Deborah J.
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Antigens
Cell adhesion & migration
Cell Differentiation
Cell Movement
Cell surface
Cells, Cultured
Cellular Reprogramming Techniques
chemokine
Chemokines
Chemokines - metabolism
Cytokines
Dermis
Differentiation (biology)
Flow cytometry
G protein-coupled receptors
GPCR
Helper cells
Humans
Infections
Inflammation
Inflammation - immunology
integrin
Integrin alphaVbeta3 - metabolism
interstitial motility
Ligands
Lymphocyte Activation
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Motility
skin
STAT6
Stat6 protein
STAT6 Transcription Factor - metabolism
Th differentiation
Th1
Th1 Cells - immunology
Th2
Th2 Cells - immunology
Tissues
Variance analysis
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Summary:T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factor-dependent programming of integrin αVβ3 expression: Th2 cell differentiation led to high αVβ3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of αVβ3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of αVβ3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues. [Display omitted] •Differential dependency on chemokines for Th1 and Th2 cell interstitial migration•Th differentiation programs elevated αVβ3 integrin expression on Th2 cells•Increased αVβ3 integrin is sufficient to facilitate chemokine-independent migration•Th1 and Th2 programming for distinct modes of migration optimizes effector function Immune responses are functionally tailored to best contain a specific pathogen challenge. T cells differentiate into functionally distinct subsets (Th1, Th2, Th17) defined by discrete cytokine production. Gaylo-Moynihan et al. find that functional specialization also extends to the navigation system used by T cell subsets to efficiently migrate within infected tissues.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2019.06.026