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The clonal selection theory dictates that antigen-specific precursor T cells exist at extremely low
frequency, but respond to antigenic challenge by multiple cycles of proliferation,
resulting in large clones of activated effector cells.
When the antigenic challenge has been neutralized, these activated cells are no longer useful,
but they occupy space, inhibit the activation of other T cells, consume resources and may be
dangerous due to their secretion of inflammatory molecules and their cytotoxic activity.
It is therefore essential that these activated T cells are removed from the immune system.
My laboratory studies the programmed cell death and removal of activated T cells.
Late in their activation cycle, T cells express a number of Death Receptors including CD95 (Fas),
and become susceptible to apoptosis induced by the ligation of these receptors.
Activated T cells are differentially susceptible to Fas-induced death signals at different
stages of the cell cycle, and we are interested in how death susceptibility is modulated.
Signaling through death receptors activates a family of apoptosis-associated enzymes termed caspases,
one of which cleaves many of the cell cycle control proteins involved in the G1/S checkpoint.
Such dysregulation of the checkpoint may contribute to cell death.
T cell apoptosis does not occur uniformly throughout the immune system.
Instead, apoptotic CD8+ T cells are selectively concentrated in the liver.
We are interested in how the liver accumulates T cells, how they are killed in this organ,
and what implications this has for liver immunobiology, particularly in relation to clinical
problems such as liver transplantation and resistance to viral hepatitis.
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Research Papers
Cao, Q., Y. Xia, et al. "The E2F-1 transcription factor promotes
caspase-8 and bid expression, and enhances Fas signaling in T cells." J
Immunol 173(2): 1111-7, 2004.
John, B. and I. N. Crispe. "TLR-4 Regulates CD8+ T Cell Trapping in the Liver." J Immunol 175(3): 1643-50, 2005.
Murray, D. A. and I. N. Crispe. "TNF-alpha controls intrahepatic T cell
apoptosis and peripheral T cell numbers." J Immunol 173(4): 2402-9,
2004.
Wright, K. O., D. A. Murray, et al. "Quantitative PCR for Detection of the OT-1 Transgene." BMC Immunol 6(1): 20, 2005.
John B, Crispe IN.
Passive and active mechanisms trap activated CD8+ T cells in the liver.
J Immunol. 172:5222-9, 2004.
Laouar Y, Crispe IN, Flavell RA.
Overexpression of IL-7R alpha provides a competitive advantage during early T-cell development.
Blood 103:1985-94, 2004.
Huleatt JW, Cresswell J, Bottomly K, Crispe IN.
P27kip1 regulates the cell cycle arrest and survival of activated T lymphocytes in response to interleukin-2 withdrawal.
Immunology 108:493-501, 2003.
Klugewitz K, Blumenthal-Barby F, Schrage A, Knolle PA, Hamann A, Crispe IN.
Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and
suppression of IFN-gamma-producing cells after intravenous protein immunization.
J Immunol. 169:2407-13, 2002.
Bi B, Littlewood NK, Crispe IN.
Cleavage of E2F-1-regulating proteins and activation of E2F-1 during
CD95-induced death of thymocytes.
Immunology 104:37-42, 2001.
Mehal WZ, Azzaroli F, Crispe IN. Antigen presentation by liver cells controls
intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially
promote intrahepatic T cell apoptosis. J Immunol. 167:667-73, 2001.
Dao T, Exley M, Mehal WZ, Tahir SMA, Snapper S, Taniguchi M, Balk SP, Crispe IN.
Involvement of CD1 in Peripheral Deletion of T Lymphocytes is independent of NK-T cells.
J. Immunol. 166:3090-3097, 2001.
Doyle IS, Hollmann CA, Crispe IN, Owens T.
Specific Blockade by CD54 and MHC II of CD40-mediated Signaling for B cell Proliferation and Survival.
Exp. Cell. Res. 265:312-318, 2001.
Bae YM, Crispe IN.
Differential Regulation of Cell Cycle-Related Proteins by CD95 Engagement in
Thymocytes and T Cell Leukemic Line, Jurkat.
J. Cell. Biochem. 80:328-338, 2001.
Laouar Y, Crispe IN.
Functional flexibility in T cells: independent regulation of CD4+ T cell proliferation and effector function in vivo.
Immunity 13:1-20, 2000.
Hingorani R, Bi B, Dao T, Bae Y, Matsuzawa A, Crispe IN.
CD95/Fas signaling in T lymphocytes induces the cell cycle control protein p21cip-1/WAF-1, which promotes apoptosis.
J Immunol. 164:4032-4036, 2000.
Review Articles
Topham DJ, Crispe IN. Contrasting urban and rural lifestyles of memory CD8+ T cells.
Immunity 18:584-6, 2003.
Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol.3:51-62, 2003.
Park S, Murray D, John B, Crispe IN.
Biology and significance of T-cell apoptosis in the liver.
Immunol Cell Biol. 80:74-83, 2002.
Mehal WZ, Azzaroli F, Crispe IN.
Immunology of the healthy liver: Old Questions and New Insights.
Gastroenterology 120:250-260, 2001.
Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. The liver as a site of T-cell
apoptosis: graveyard, or killing field? Immunol Rev. 174:47-62, 2000.
Crispe IN.
Do natural T cells promote liver regeneration?
Hepatology 31:1022-4, 2000.
Publication list, as provided by PubMed.
PubMed is maintained by the National Library of Medicine
and provides complete abstracts of all publications, as well as links
to the full text of many articles (at journal homepages).
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