TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells (1)
Members of the T-cell immunoglobulin– and mucin-domain–containing molecule (TIM) family have roles in T-cell–mediated immune responses. TIM-1 and TIM-2 are predominantly expressed on T helper type 2 (Th2) cells, whereas TIM-3 is preferentially expressed on Th1 and Th17 cells. Especially, TIM-1 enhances and TIM-2 suppresses T helper type 2 (Th2) cell activation, and TIM-3 down-regulates Th1 cell function. Mice treated with an anti–TIM-1 Ab or a TIM-1 extracellular domain protein exhibited attenuated development of antigen-induced airway inflammation and of contact or delayed-type hypersensitivity responses. Blockade of the TIM-3 pathway exacerbated experimental autoimmune encephalomyelitis, diabetes (in nonobese diabetic mice), and acute graft-versus-host disease.
Bone marrow–derived cultured mast cells (BMCMCs) were obtained by culturing mouse bone marrow cells in WEHI-3–conditioned medium (containing interleukin-3 [IL-3]) for 4 to 6 weeks. Naive BMCMCs from C57BL/6J mice constitutively expressed TIM-1, as detected by anti–TIM-1 mAbs (3B3, RMT1-4, or RMT1-17) . Similar results were obtained with C57BL/6Ka, BALB/cJ, or BALB/cKa BMCMCs. BALB/cJ mouse peritoneal mast cells (PMCs) constitutively express TIM-3, based on staining with the 8B.2C12 anti–TIM-3 mAb: the 8B.2C12 antibody does not recognize the TIM-3 allele expressed in the C57BL/6J background. However, the RMT3-23 anti–TIM-3 mAb detected constitutive expression of TIM-3 on C57BL/6J, C57BL/6Ka, BALB/cJ, or BALB/cKa BMCMCs.
Neither anti–TIM-1 pAbs nor mAbs (RMT1-4, RMT1-17, 3B3, or 222414), rmTIM4 nor anti–TIM-3 pAbs or mAbs (RMT3-23, 8B.2C11, or 215015) detectably influenced degranulation or phosphorylation of ERK1/2, JNK, or MAPK after IgE and Ag stimulation in any of the C57BL/6J BMCMCs tested. However, anti–TIM-3 pAb, but not anti–TIM-3 mAbs (RMT3-23, 8B.2C12, or 215015), significantly enhanced IL-4, IL-6, and IL-13 production by IgE + Ag–stimulated BMCMCs. Results similar to in C57BL/6J were also obtained in BALB/cJ BMCMCs. Anti–TIM-3 mAbs (RMT3-23 or 8B.2C12) functioned as blocking Abs, whereas anti–TIM-3 pAb had agonist effects.
Anti–TIM-3 mAbs (RMT3-23 or 8B.2C12) functioned as blocking Abs, whereas anti–TIM-3 pAb had agonist effects.