TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4(+) regulatory T cells (Treg cells). Less is known about the function of CD8(+) Treg cells than about the function of CD4(+) Treg cells generated during allergen-specific immunotherapy ( IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8(+)CD25(+)Foxp3(+) Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8(+)Foxp3(+) Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8(+)CD25(+)Foxp3(+) Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8(+)CD25(+) Treg cells directly suppressed CD4(+) T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8(+)CD25(+) Treg cells, but not CD4(+)CD25(+) Treg cells, directly induced CD4(+)CD45RO(hi+) apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8(+) Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies. The Journal of Immunology, 2010, 184: 7229-7237.