Granulocyte chemotactic protein‐2 mediates adaptive immunity in part through IL‐8Rβ interactions

Chemokines constitute a large family of structurally related proteins that play a role in leukocyte migration and differentiation. Indeed, the early expression of human CXC chemokine receptor 1 (hCXCR1) and hCXCR2 [homologous to mouse interleukin (IL)‐8Rβ] ligands by the epithelium is a hallmark of the mucosal host defense. Mice lack IL‐8; however, granulocyte chemotactic protein‐2 (GCP‐2)/lipopolysaccharide‐induced CXC chemokine, a murine homologue of human GCP‐2, has 32% and 61% sequence identity to human IL‐8 and GCP‐2, respectively, and binds hCXCR1, hCXCR2, and mouse IL‐8Rβ. To better understand the role of GCP‐2 in adaptive immunity and as a nasal adjuvant, we characterized the exogenous effects of this CXC chemokine on cellular and humoral mucosal immune responses. GCP‐2 significantly enhanced serum immunoglobulin G (IgG) and mucosal IgA antibodies through increased cytokine secretion by CD4 + T cells. These alterations in humoral and cellular responses were preceded by an increase in the number of B cells in the nasal tract, a decrease in the number of CD4 + T cells in the nasal tract as well as cervical lymph nodes, and an increase in the number of neutrophils in the nasal tract 12 h after GCP‐2 immunization. This chemokine also modulated CD28 expression by CD4 + T cells during CD3ɛ stimulation of wild‐type mice. GCP‐2 increased CD80 and CD86 expression on B cells during in vitro stimulation in a dose‐dependent manner. In contrast, cytokine and costimulatory molecule enhancement by GCP‐2 was not induced by lymphocytes from IL‐8Rβ −/− mice, suggesting that GCP‐2 modulates cellular immunity in part through IL‐8Rβ interactions.