Beta chemokines costimulate lymphocyte cytolysis, proliferation, and lymphokine production.
We report here the ability of the beta chemokines MIP-1 alpha, MIP-1 beta, RANTES, and MCP-1 to enhance some lymphocyte effector functions. Initial studies focused on the effects of chemokines on human and mouse cytotoxic T lymphocyte (CTL)- and natural killer (NK) cell-specific cytolytic responses. The results demonstrate that beta chemokines are capable of augmenting mouse and human CTL and human NK- but not lymphokine-activated killer cell- or antibody-dependent cell cytotoxicity-specific cytolytic responses. Neutralization analysis utilizing integrin-specific antibodies revealed that CTL/NK tumor cell conjugate formation is required for chemokine-induced killing. In addition, both CTLs and NK cells incubated with various beta chemokines were induced to degranulate and release granule-derived serine esterases, suggesting that chemokines may be important costimulators of CTL and NK cell degranulation and may thus augment local target cell destruction. Chemokines also modulate antigen-driven T cell proliferative responses as well as effects on lymphokine production. Many of the beta chemokines were found to potentiate human and mouse antigen-specific Th1 and Th2 clone activation promoting cellular proliferation and the release of various lymphokines. This chemokine-mediated T cell proliferation was chemokine and antigen dose dependent as well as clone dependent. Chemokine pretreatment analyses with T cells and antigen-presenting cells (APCs) revealed that chemokines up-regulate both T cells and antigen- presenting cells (APCs) revealed that chemokines up-regulate both T cell and APC functions. Costimulation assays using immobilized antiCD3 monoclonal antibody-coated plates and purified human and mouse T cells and T cell clones in the presence of various chemokines also exhibited enhanced proliferation and lymphokine secretion. This costimulation was interleukin-2 dependent and required the presence of free extracellular calcium. Examination of chemokine-treated APCs revealed that the T cell costimulatory molecule B7-1 was induced by various beta chemokines. Neutralization of endogenously produced chemokines, with specific antibodies during an antigen-specific T cell response blocked cellular proliferation, suggesting that the chemokines have an autocrine role in antigen-induced T cell proliferative responses. Together, these results suggest that chemokines play a significant role in the activation of polyclonal as well as antigen-specific helper and cytotoxic T cells during the genesis of an immune response.
Taub
D D
DD
Clinical Services Program, SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Ortaldo
J R
JR
Turcovski-Corrales
S M
SM
Key
M L
ML
Longo
D L
DL
Murphy
W J
WJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D018925:Chemokines / Q000494:pharmacology* / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology; D008222:Lymphokines / Q000096:biosynthesis*; D051379:Mice; D013268:Stimulation, Chemical; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D018925:Chemokines; D008222:Lymphokines