Mast Cells Control Neutrophil Recruitment during T Cell–Mediated Delayed-Type Hypersensitivity Reactions through Tumor Necrosis Factor and Macrophage Inflammatory Protein 2

TLDR

Polymorphonuclear leukocytes infiltrate skin, joint, and gut delayed‑type hypersensitivity reactions driven by IFNγ‑producing type 1 T cells, but are absent in brain or pancreas DTHRs. The study aimed to identify the cells and mediators that recruit PMNs into skin, joint, or gut during T cell‑mediated DTHRs. Mast cells orchestrate T cell‑dependent PMN recruitment via tumor necrosis factor and the chemokine MIP‑2, which is abundant in wild‑type but missing in mast‑cell‑deficient mice. Blocking MIP‑2 or depleting mast cells reduced PMN recruitment by >60–80 %, and only mast cells from wild‑type mice, not TNF‑deficient ones, restored DTHRs, confirming mast‑cell‑derived TNF and MIP‑2 dictate infiltrating cell patterns.

Abstract

Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell–mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell–mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon γ–producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell–dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell–deficient WBB6F1-KitW/KitW-v (KitW/KitW-v) mice. T cell–dependent PMN recruitment was reduced >60% by anti–MIP-2 antibodies and >80% in mast cell–deficient KitW/KitW-v mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2–dependent PMN recruitment in KitW/KitW-v mice, whereas mast cells from TNF−/− mice did not. Thus, mast cell–derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell–mediated DTHRs.