TY - JOUR
T1 - Staphylococcal enterotoxin B-induced activation and concomitant resistance to cell death in CD28-deficient HLA-DQ8 transgenic mice
AU - Rajagopalan, Govindarajan
AU - Smart, Michele K.
AU - Marietta, Eric V.
AU - David, Chella S.
N1 - Funding Information:
We thank Julie Hansen and her crew for mouse husbandry. This study was supported by NIH grant AI14764.
PY - 2002
Y1 - 2002
N2 - 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-γ 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 proliferation, 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-γ. 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.
AB - 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-γ 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 proliferation, 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-γ. 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.
KW - Co-stimulatory molecule
KW - MHC
KW - Rodent
KW - Superantigen
KW - Transgenic/knockout
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U2 - 10.1093/intimm/dxf047
DO - 10.1093/intimm/dxf047
M3 - Article
C2 - 12096040
AN - SCOPUS:0036316778
SN - 0953-8178
VL - 14
SP - 801
EP - 812
JO - International Immunology
JF - International Immunology
IS - 7
ER -