CAML in T cell Development and Function

Project: Research project

Description

Thymocyte development is a remarkable process that balances the need for large numbers of peripheral T
cells bearing a highly diverse repertoire with the requirement that potentially dangerous "self-reactive" T cells
not survive. The molecular mechanisms that underlie this process are not completely understood. It is
essential to learn more about thymocyte development because defects in this process underlie many human
diseases, including immunodeficiency and auto-immunity, and may play a role in cancer resulting from
inadequate immune surveillance. This proposal focuses on the intracellular integral membrane protein CAML
(Calcium Modulating cyclophilin Ligand). We seek to learn its role and mechanism of action in T cell
development and function.
We originally identified the CAML gene in a two-hybrid interaction screen using cyclophilin B as bait. In the
previous grant funded period, we generated CAML knockout mice, and determined that the gene is required
for early embryonic development. We discovered an essential role for CAML in mediating the proliferative
effects of the Epidermal Growth Factor Receptor (EGFR), and identified a direct interaction between CAML
and the kinase domain of EGF-activated EGFR.
We recently published new data revealing a critical role for CAML in thymocyte development. We generated
CAML-conditional knockout mice and disrupted the gene specifically in developing T cells by the use of an
Lck-Cre transgene. We found that loss of CAML causes a defect during thymopoiesis and essentially
complete failure to produce peripheral T cells. This, together with the finding that Jurkat T leukemia cells
engineered to express a dominant negative form of CAML show increased apoptosis, suggests a role for
CAML in regulating T cell development, possibly through effects on survival. We have also discovered that
CAML interacts with p56Lck, a protein kinase with established roles in T cell development, proliferation, and
activation-induced apoptosis, and show that CAML is required for efficient p56Lck-dependent activation of
the downstream signaling kinase ERK.
Our central hypothesis is that CAML provides an essential function during two stages of T cell development,
and that the mechanism is via enhanced resistance to apoptosis through its effects on p56Lck. To elucidate
the biological mechanism of CAML in T cell development and function at the molecular, cellular, and
organismal levels, we propose experiments to further investigate the precise steps in thymocyte
development that are defective in the absence of the gene. In addition, we will conduct biochemical and
structural experiments to determine the mechanism by which CAML regulates Lck and Erk signaling, and to
discover how these enable T cells to develop and function.
StatusFinished
Effective start/end date12/16/996/30/13

Funding

  • National Institutes of Health: $381,805.00
  • National Institutes of Health: $339,975.00
  • National Institutes of Health: $339,975.00
  • National Institutes of Health: $336,575.00
  • National Institutes of Health: $30,878.00
  • National Institutes of Health: $339,975.00

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Cyclophilins
Ligands
Calcium
T-Lymphocytes
Thymocytes
Apoptosis
Epidermal Growth Factor Receptor
Knockout Mice
Genes
Phosphotransferases
Neoplasms
Immune System
Intracellular Membranes
Organized Financing
T-Cell Leukemia

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)