tumor cell biology program - Sylvester Comprehensive Cancer Center

which occurs by a novel proteasome dependent
pathway. 3) IL-7 and IL-15 were
found to be the essential γc-dependent
cytokines important for thymic-dependent
T cell development while IL-2, IL-
7 and IL-15 are required for the full
production of intraepithelial T lymphocytes,
a second anatomical site of T
cell development. 4) They have used
transgenic and gene knockout mouse
models to define the molecular basis by
which IL-7R regulates T cell development.
These studies indicate that separate
cytoplasmic domains of the IL-7Rγ
chain differentially control distinct functions
during T cell development, while
normal IL-7R-dependent thymic development
requires the integrated activity
of all these domains. 5) They have uncovered
a novel and unexpected role for
IL-2 in thymic development, which is
essential to prevent autoimmunity.
6) This work illustrates that one important
reason for failed anti-tumor immunity
is that tumor-specific T cells are
ignorant of the growing tumor. Importantly,
a dendritic cell-based vaccine potently
functioned to induce tumor
immunity, which sometimes may lead to
the rejection of the tumor.
PUBLICATIONS
Malek, TR, Porter, BO and He, Y-
W. Regulation of T lymphocyte development
by γc dependent cytokines.
Immunology Today 20:71, 1999.
Porter, BO and Malek, TR. Prostaglandin
E2 inhibits T cell activationinduced
apoptosis and Fas-mediated
cellular cytotoxicity by blockade of Fas-
L. European Journal of Immunology
29:2360, 1999.
Maramor, MD, Bachmann, MF,
Ohashi, PS, Malek, TR and Julius, M.
Immobilization of GPI-anchored proteins
inhibits T cell growth but not function.
International Journal of Immunology
11:1381, 1999.
Porter, BO and Malek, TR. IL-2Rβ/
IL-7Rα doubly deficient mice recapitulate
the thymic and intraepithelial lymphocyte
(IEL) developmental defects of
γc-/- mice: Roles for both IL-2 and IL-
15 in CD8 IEL development. Journal of
Immunology 163:5906, 1999.
Li, XC, Ima, A, Li, Y, Zheng, XX,
Malek, TR and Strom, TB. Blocking the
common gamma-chain of cytokine receptors
induces T cell apoptosis and longterm
islet allograft survival. Journal of
Immunology 164:1193, 2000.
Malek, TR, Porter, BO, Codias, EK,
Scibelli, P and Yu, A. Normal lymphoid
homeostasis and lack of lethal autoimmunity
in mice containing mature T cells
with severely impaired IL-2 receptors.
Journal of Immunology 164:2905, 2000.
Codias, EK, Olosz, F and Malek,
TR. Genomic organization and 5’ regulatory
region of the mouse interleukin 2
receptor beta-chain gene (IL-2Rb). Immunogenetics
51:508, 2000.
Dalyot-Hermans, N, Bathe, O and
Malek, TR. Reversal of CD8(+) T cell
ignorance and induction of anti-tumor
immunity by peptide-pulsed APC. Journal
of Immunology 165:673, 2000.
Olosz, F and Malek, TR. Three
loops of the common gamma chain
ectodomain required for the binding of
interleukin-2 and interleukin-7. Journal
of Biological Chemistry 275:30100,
2000.
Porter, BO and Malek, TR. Thymic
and intestinal intraepithelial T lymphocyte
development are each regulated by
the gamma c-dependent cytokines II-2,
IL-7, and IL-15. Seminars in Immunology
12:465, 2000.
Yu, AX, Olosz, F, Choi, CY and
Malek, TR. Efficient internalization of
IL-2 depends on the distal portion of the
cytoplasmic tail of the IL-2R common
gamma-chain and a lymphoid cell environment.
Journal of Immunology
165:2556, 2000.
Li, XC, Demirci, G, Ferrari-Lacraz,
S, Groves, C, Coyle A, Malek, TR and
Strom, TB. IL-15 and IL-2: a matter of
life and death for T cells in vivo. Nature
Medicine 7:114, 2001.
Malek, TR, Yu, AX, Scibelli, P,
Lichtenheld, MG and Codias, EK. Broad
programming by IL-2 receptor signaling
for extended growth to multiple
cytokines and functional maturation of
antigen-activated T cells. Journal of Immunology
166:1675, 2001.
Porter, BO, Scibelli, P and Malek,
TR. Control of T cell development in
vivo by subdomains within the IL-7 receptor
alpha-chain cytoplasmic tail. Journal
of Immunology 166:262, 2001.
Yu, AX and Malek, TR. The
proteasome regulates receptor-mediated
endocytosis of interleukin-2. Journal of
Biological Chemistry 276:381, 2001.
Eckhard R. Podack, M.D., Ph.D.
Chairman and Professor of
Microbiology and Immunology
DESCRIPTION OF RESEARCH
Perforin is one of the cytotlytic molecules
critical for tumor rejection
and viral defense. Creating perforindeficient
mice with a combined deficiency
for Fas-ligand (Fas-L) resulted in
early death of double deficient mice due
to uncontrolled expansion of cytotoxic
T cells (CTL) and monocytes/macrophages
and destruction of the pancreas and
uterus. The function of perforin in homeostasis
in the absence of Fas-L is the
removal antigen presenting cells by activated
CTL and thereby terminating the
immune response.
Negative regulators of CTL activity
(with H. Muta)
CTL are potent effectors of the immune
system. Their uncontrolled activation
and proliferation leads to severe disease
and death as described above. Several
molecules, including Fas-L and other
death ligands, CTLA4 and TNF, are
known to be involved in down regulation
of CTL. They have discovered that
CD30, a molecule transiently expressed
on activated CTL can provide powerful
negative regulation to suppress CTL.
CD30 signals turn off cytotoxicity by
suppressing Fas-L, perforin, and
granzyme B expression. Proliferation of
CTL is terminated by CD30 through
30
UM/Sylvester Comprehensive Cancer Center Scientific Report 2002