Role of natural killer T (NKT) cells lacking interleukin (IL)-4 producing abilities on the CC-chemokine ligand 2-associated herpes simplex virus type 1 infection in human severe combined immunodeficiency (SCID) mouse chimeras

CC-chemokine ligand 2 (CCL2/monocyte chemoattractant protein 1) is known to have an important role on T helper type 2 (Th2) cell generation and described to induce interleukin (IL)-4 production by activated T cells. In the present study, an increase of CCL2 production in cultures of peripheral blood lymphocytes (PBL) from patients with severe thermal injuries was demonstrated. Severe combined immunodeficiency (SCID) mice reconstituted with PBL from healthy donors (PBL-SCID chimeras) were resistant to infection with herpes simplex virus type 1 (HSV-1). Treatment of these chimeras with recombinant human CCL2 resulted in an increased susceptibility to the same HSV-1 infection. However, human SCID mouse chimeras created by PBL depleted of natural killer T (NKT) cells (NKT^- PBL-SCID chimeras) were resistant to HSV-1 infection, even though they were treated with CCL2. IL-4 was not detected in the sera of NKT^- PBL-SCID chimeras treated with CCL2, while IL-4 was detected in the sera of PBL-SCID chimeras under the same CCL2 administration. NKT cells isolated from PBL were shown to be cells not responsible for CCL2-stimulated IL-4 production. However, in the presence of CCL2, IL-4 was detected in culture fluids of NKT cells co-cultured with naive T cells. This cytokine was produced in co-cultures of NKT cells pretreated with CCL2 (CCL2-NKT cells) and naive T cells. In addition, IL-4 production was demonstrated in transwell cultures of CCL2-NKT cells and naive T cells. These results suggest that NKT cells lacking IL-4 producing abilities contribute to the CCL2-associated increase in the susceptibility of thermally injured patients to HSV-1 infection through the induction of Th2 cell generation.