The lymphoid chemokine CCL21 costimulates naive T cell expansion and Th1 polarization of non-regulatory CD4+ T cells.
CCL21 (SLC/6Ckine) is constitutively expressed by secondary lymphoid tissue and attracts CCR7-expressing mature dendritic cells and naive T cells. Recent studies demonstrated that intra-tumoral delivery of CCL21 induces tumor regression in a T cell dependent manner. CCL21 is known to mediate T cell trafficking but little is known about its function as a costimulatory molecule. Herein, we demonstrate that CCL21 costimulates expansion of CD4+ and CD8+ T cells and induces Th1 polarization. These effects were specific for naive T cells, and we show that CD4+CD25+ regulatory T cells were hyporesponsive to CCL21 induced migration, and unresponsive to CCL21 costimulation. These unique functions of CCL21 to both attract naive T cells as well as costimulate their proliferation and differentiation, suggests that CCL21 is a pivotal molecule for priming T cell responses and has therapeutic implications for local delivery of CCL21. The coordinated effects of CCL21 on T cell migration and activation may also represent a more comprehensive paradigm for the activity of other chemokines as well.
Flanagan
Kenneth
K
Department of Pathology, Columbia University, New York, NY 10032, USA.
Moroziewicz
Dorota
D
Kwak
Heesun
H
Hörig
Heidi
H
Kaufman
Howard L
HL
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016764:Cell Polarity / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects*
D015704:CD4 Antigens; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1