Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse.
Hyaluronan (HA) production by dendritic cells (DCs) is known to promote antigen presentation and to augment T-cell activation and proliferation. We hypothesized that pericellular HA can function as intercellular 'glue' directly mediating T cell-DC binding. Using primary human cells, we observed HA-dependent binding between T cells and DCs, which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone (4-MU), an agent which blocks HA synthesis. Furthermore, T cells regulate HA production by DCs via T cell-derived cytokines in a T helper (Th) subset-specific manner, as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production. Similar effects were seen upon the addition of exogenous Th1 cytokines, IL-2, interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). The critical factors which determined the extent of DC-T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA, as T-cell clones which were pre-treated with monensin, added to block cytokine secretion, bound equivalently irrespective of their Th subset. These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA, which in turn affects the extent of DC-T cell binding. We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation. These data point to a pivotal role for HA in DC-T cell interactions at the IS.
Bollyky
Paul L
PL
Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, USA. pbollyky@benaroyaresearch.org
Evanko
Stephen P
SP
Wu
Rebecca P
RP
Potter-Perigo
Susan
S
Long
S Alice
SA
Kinsella
Brian
B
Reijonen
Helena
H
Guebtner
Kelly
K
Teng
Brandon
B
Chan
Christina K
CK
Braun
Kathy R
KR
Gebe
John A
JA
Nepom
Gerald T
GT
Wight
Thomas N
TN
D002448:Cell Adhesion; D048430:Cell Shape; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D016207:Cytokines; D006820:Hyaluronic Acid