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Tales from the crypt
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. Both reagents promoted differentiation and
inhibited proliferation in the two cell lines, indicating that Nox1
functioned in differentiation and not mitogenesis. Superoxide
production was restored in differentiated Nox1-transduced PLB-985 cells
after PMA stimulation, demonstrating that Nox1 can reconstitute the
disrupted gp91phox gene in the PLB-985 cells.
Cotransduction of Nox1 and two other subunits of NADPH oxidase,
p47phox and p67phox,
restored a low level of superoxide production in K562 erthroleukemia
cells lacking gp91phox,
p47phox, and p67phox but
expressing p22phox. Thus, Nox1 functionally
interacted with other phox components. Transduced Nox1
partially corrected the gp91phox deficiency in
stem cells from patients with X-linked chronic granulomatous disease,
indicating a possible avenue of therapy for that disease. FADD
The adaptor protein, Fas-associated death domain (FADD), is required for T cell apoptosis. Unexpectedly, FADD mutant mice have been found to be defective in T
cell activation. In an investigation into the involvement of FADD in
cell cycle events, Beisner et al. (p. 247
) used transgenic mice
carrying a dominant-interfering form of FADD (FADDdd) that blocked FADD
signaling. They found that FADDdd mice had reduced numbers of
CD4+ T and CD8+ T cells compared with wild-type
mice. CD8+ T cells from FADDdd mice were incapable of being
activated by anti-CD3 Ab, even in the presence of IL-2, IL-4, or
anti-CD28 Ab. CD4+ T cells from FADDdd mice were
activated under those conditions but to a lesser extent than
CD4+ T cells from wild-type mice. All T cells from FADDdd
mice had functional IL-2 receptors and treatment with anti-CD3 Ab
led to the induction of phospho-STAT. However, FADDdd
CD8+ T cells had higher death rates than either wild-type
or FADDdd CD4+ T cells. Wild-type CD8+ T cells
transduced with either of two FADDdd expression vectors failed to
proliferate, and FADDdd mice infected with a strain of LCMV exhibited a
reduction in splenic CD4+ T cells and an absence of
CD8+ T cells compared with virus-infected wild-type mice.
The authors suggest that the FADD pathway is involved in regulating T
cell responses and is required for the survival of activated mature T
cells. {itititle}NOD defects {ititexf}A possible cure for type 1 diabetes
is transplantation of pancreatic islet cells. However, the NOD mouse, a
model for autoimmune diabetes, is resistant to a costimulation
blockade-based transplantation tolerance protocol. The possibility that
autoimmunity and resistance to transplantation tolerance are controlled
separately in NOD mice would lessen the relevance of NOD-based
transplantation protocols for human therapy. Pearson et al. (p. 185
)
generated several strains of (NOD x C57BL/6)F1 mice
to study the genetic factors involved in transplantation tolerance and
autoimmunity. Skin allografts on NOD and diabetes-resistant
F1 mice, all treated with anti-CD154 mAb plus
donor-specific transfusion, survived for shorter times than on
similarly treated C57BL/6 (B6) mice. CD8
-/- strains of
NOD and F1 mice retained skin allografts for shorter times
than did CD8-/- B6 mice. Dendritic cell maturation was
defective in both NOD and F1 mice compared with B6 mice. In
contrast, the cytotoxic activity of NK spleen cells and IL-1
production of LPS-stimulated macrophages from F1 and B6
mice were much higher than those of NK spleen cells and LPS-stimulated
macrophages from NOD mice. The data demonstrate separate genetic
control of autoimmunity and transplantation tolerance in NOD mice and
suggest that conclusions based on tolerance induction studies in the
NOD model may not be applicable to humans.
Cytokines and T cell homeostasis
|
-chain receptor cytokines in polyclonal T cell homeostasis and
Fas-mediated apoptosis is not clear. Jaleco et al. (p. 61
)
studied the role of two of those cytokines, IL-2 and IL-7, on T cell
homeostasis. Populations of naive CD4+ T cells
(TN) and memory CD4+ T cells (TM)
were purified from human adult peripheral blood. Recent thymic
emigrants (RTE) were isolated from human umbilical cord blood. RTE, but
not TN or TM, progressed through at least three
cell divisions in the presence of IL-7 or IL-2 alone; the number of
cell divisions was increased greatly when the cells were treated with
IL-2 and IL-7 at the same time. Incubation with both cytokines, but not
with either cytokine alone, led to enhanced levels of Fas expression
and cell death in RTE and TN. Fas-mediated cell death was
inhibited by the addition of a caspase-inhibitor to these cells
stimulated by IL-2 and IL-7 together. No increase in Fas expression and
only a slight increase in cell death were seen in TM
exposed to both cytokines. STAT 5 phosphorylation was
higher in IL-2-stimulated TM compared with TN
or RTE whereas IL-7 induced higher levels of STAT5
phosphorylation in TN and RTE than in
TM. The data indicate that IL-2 and IL-7 differentially
regulate CD4+T cell subset proliferation and
apoptosis. Arthritis susceptibility loci
|
Memories
Effector CD8+ T cells rapidly kill
pathogen-infected cells during primary infections. However, it is
unclear to what extent memory CD8+ T cells arising from
effector CD8+ T cells can respond to subsequent infections
by the same agent. Barber et al. (p. 27
) and Byers et al. (p. 17
)
labeled splenocytes from naive mice with fluorescent markers and coated
them with peptides from lymphocytic choriomeningitis virus (LCMV) or
from type A2 polyoma virus (A2), respectively. Injection of target
cells labeled with virus-specific peptides into mice at the peak (seven
to eight days) of virus infection resulted in killing of up to 75% of
the LCMV target cells within 15 min and 95% of the A2 target cells
within 4 h. Perforin-/- mice were impaired in their
killing of both LCMV and A2 peptide-coated target cells as compared
with wild-type mice, whereas no differences in target elimination were
seen in fas-/- or TNF--/- mice vs
wild-type controls. LCMV and A2 immune mice began killing their
respective coated target cells as early as 15 min after injection.
Cytotoxic activity of the LCMV memory CD8+ T cells was
stable over 198 days. Both groups showed that memory CD8+ T
cells briefly lagged behind the effector CD8+ T cells in
killing activity. The results indicate that memory CD8+ T
cells can rapidly kill cells in second encounters with an infectious
agent.
LT/LIGHT axis
Lymphotoxin (LT), expressed on the surface of B cells,
helps maintain specialized microenvironments in secondary lymphoid
organs. LT and a second ligand, LIGHT, bind to the LTB receptor
(LTR). Fava et al. (p. 115
) looked at the role of the LT/LIGHT axis
in development and progression of collagen-induced arthritis (CIA).
They used a LTR-Ig fusion protein (LTR-Ig) as a decoy receptor to
block activation of LTR by the ligands. DBA-1 mice treated with
LTR-Ig for two weeks before immunization with type II collagen (CII)
failed to develop clinical signs of arthritis. Mice injected with
LTR-Ig the same day CII immunization was begun developed less severe
disease compared with untreated immunized controls. Progression of
established CIA was halted by administration of LTR-Ig 5 wk
after CII immunization. Follicular dendritic networks and germinal
centers in the spleen and draining lymph nodes were eliminated by
LTR-Ig pretreatment but were present in high numbers in untreated
CII immunized mice. The number of Ab secreting cells in the draining
lymph nodes of LTR-Ig treated mice was reduced compared with
untreated CIA controls. The data demonstrate that LTR-Ig is
effective in blocking development of a complex autoimmune disease, CIA,
at multiple levels. The LT/LIGHT axis could serve as a therapeutic
target for treatment of rheumatoid arthritis.
Summaries written by Dorothy L. Buchhagen, Ph.D.
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