CTLA-4 may deliver a positive T cell costimulatory signal at the initiation of a TH2 immune response in vivo

T cell activation leading to Th2 cytokine production requires costimulatory signals provided by B7 ligands. Although CD28 signaling is thought to provide this positive signal, Th2 immune responses to pathogens are frequently intact in CD28 deficient mice, although these same responses are blocked following CTLA-4Ig administration in normal mice. We have previously reported this apparent paradox during the mucosal Th2 immune response to /italicizeH. polygyrus(HP). In the studies reported here, BALB/c CD28-/- and CD28+/+ HP-inoculated mice were administered anti-CTLA-4 mAb at the time of oral inoculation. Elevations in mesenteric lymph node (MLN) CD4+ T cell IL-4 gene expression and protein secretion were blocked in HP-inoculated CD28-/-, but not HP-inoculated CD28+/+, mice administered anti-CTLA-4 mAb. Similarly, T cell dependent elevations in MLN GC formation, serum IgE and IgGl levels were also blocked in HP-inoculated CD28-/-, but not CD28+/+, mice given anti-CTLA-4 mAb. CTLA-4Ig administration of HP-inoculated CD28-/- mice also inhibited T cell cytokine production and effector function. Our findings suggest that CTLA-4 may provide a positive T cell costimulatory signal during an in vivo Th2 mucosal immune response to a pathogen.