T cell immunity and cytokine receptor redundancy

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Although the specificity of a T cell
immune response is dictated by the TCR, the interaction of cytokines with their
receptors is required for the clonal expansion and differentiation of
antigen-activated T cell into effector cells, for limiting the magnitude of the
response, and for maintaining the homeostasis of naive and memory peripheral T
cells. Some of the most important cytokine receptors that regulate these
activities are those that share the common gamma chain (gamma c), i.e. the
IL-2R, IL-4R, IL-7R, IL-9R, and IL-15R. As several gamma c-dependent cytokines
function non-redundantly at the level of the thymus, it has been difficult to
unambiguously delineate what functions these cytokines play during an immune
response and in maintaining T cell homeostasis. For example, IL-7R function is
required for the production of thymic-derived T cells. Furthermore, our most
recent data demonstrate that IL-2 functions non-redundantly at the level of the
thymus to regulate self reactivity which is an important component for
IL-2-dependent maintenance of peripheral T cell homeostasis. During the last
application period, a series of thymic-targeted transgenic mice on various
cytokine or cytokine receptor knockout genetic backgrounds were produced in
which the T cell developmental defects associated with IL-2 or IL-7 were
largely corrected, but the peripheral T cell compartment remained
non-responsive to these cytokines. To investigate the redundant activity of
IL-4 with IL-2 for T cell growth and effector cell differentiation and with
IL-7 for promoting the survival of naive T cells, these transgenic mice have
been backcrossed to IL-4-/- mice. Therefore, one major objective of this
application is to establish the contribution of the IL-2R/IL-15R, IL-4R, and
IL-7R during T cell immune responses in vivo using these mouse models. We will
also investigate in vivo the relative role of these cytokine receptors for the
survival and homeostasis of naive and memory I cells. Another major objective
of the proposed studies is to determine the molecular basis by which IL-2Rbeta
signaling programs antigen-activated T cells for extended cytokine dependent
growth and differentiation into effector T cells. Our goal here is to relate
molecular targets of IL-2R signaling with specific biological responses.
StatusFinished
Effective start/end date7/1/965/31/07

Funding

  • National Institute of Allergy and Infectious Diseases: $340,875.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $340,875.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $306,788.00
  • National Institute of Allergy and Infectious Diseases: $340,875.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $340,875.00
  • National Institute of Allergy and Infectious Diseases: $224,605.00

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