Staphylococcal enterotoxin B-induced activation and concomitant resistance to cell death in CD28-deficient HLA-DQ8 transgenic mice.
HLA class II molecules present superantigens more efficiently than their murine counterpart. Therefore, transgenic mice expressing HLA-DQ8 with and without CD28 were used to address the role of CD28 in staphylococcal enterotoxin B (SEB)-driven immune responses. SEB-induced in vitro proliferation of naive DQ8.CD28(-/-) splenocytes was comparable to DQ8.CD28(+/+) cells, and was several fold higher than that of C57BL/10 and BALB/c splenocytes. SEB-activated, naive DQ8.CD28(-/-) cells in vitro produced significantly less IL-2, IL-4 and IL-10 than DQ8.CD28(+/+) cells, while IFN-gamma and IL-6 production was comparable. SEB-induced in vivo expansion of CD4(+) T cells and, to a greater extent, CD8(+) T cells was compromised in DQ8.CD28(-/-) mice, indicating that SEB-induced proliferation of CD8(+) T cells is more dependent on CD28 co-stimulation. Upon re-stimulation, SEB-primed CD28(+/+) T cells failed to proliferate but were capable of producing cytokines. Conversely, CD28(-/-) T cells were capable of proliferation, but not cytokine production. SEB-primed CD28-deficient cells produced significantly less nitric oxide when compared to CD28-sufficient cells following re-stimulation with SEB. CD28(+/+) and not CD28(-/-) mice were highly susceptible to SEB-induced lethal shock characterized by significantly elevated serum IFN-gamma. Thus, (i) efficient presentation of SEB by HLA-DQ8 circumvents co-stimulation through CD28, (ii) unique CD28-derived signals are mandatory for generation of certain effector functions, and (iii) absence of CD28-derived signals confers resistance to activation-induced cell death and protects mice from SEB-induced shock.
Rajagopalan
Govindarajan
G
Department of Immunology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA.
Smart
Michele K
MK
Marietta
Eric V
EV
David
Chella S
CS
D000818:Animals; D017951:Antigen Presentation; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D016923:Cell Death; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis; D012772:Shock, Septic / Q000276:immunology; D013154:Spleen / Q000166:cytology; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D018106:CD28 Antigens; D016207:Cytokines; D004768:Enterotoxins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D018089:Superantigens; D009569:Nitric Oxide; C031818:enterotoxin B, staphylococcal