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Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

8-2000

Committee Chair or Co-Chairs

Robert Stout

Committee Members

David S. Chi, Jill Suttles, Michael T. Gallagher, Robert V. Schoborg

Abstract

Naive T cells are positioned at the origin of adaptive immune responses. The activation of naive T cells is usually viewed from the perspective of IL-2 production and entry into the cell cycle. This activation is antigen specific and MHC restricted via TCR ligation/CD3 signaling but also demands the simultaneous ligation of and signaling via CD28. Naive T cell TCR ligation without appropriate co-stimulus produces an anergic state, in which the naive T cell fails to produce IL-2 or expand clonally. It is implied that cells that might present self-destructive antigens would be incapable of delivering required costimulus thus avoiding initiation of inappropriate immune responses. However, CD45RBhi expressing THP cells express high levels of CD40L that is sustained following extended periods of TCR/CD3 stimulation. CD40L is the major T cell molecule involved in contact-dependent signaling of both B-cell and macrophage effector functions. This suggests that naive CD4+ T cells are capable of participating in and contributing to on-going immune responses following signaling via TCR/CD3 alone. This dissertation represents efforts to analyze the contact signaling capability of naive CD4+ T cells and their ability to trigger macrophage cytocidal/tumoricidal functions.

The data generated by this research demonstrate that:

  1. Naive T cell purification by endothelial panning was superior to the standard method of CD44 panning for studies on T cell mediated macrophage activation.
  2. The activation requirements for contact signaling of macrophages by naive T cells are less stringent than the requirements for activation of naive T cell proliferation.
  3. Viable naive THP and antigen presenting splenic macrophages are capable of delivering reciprocal activating signals.
  4. Viable naive THP responding to presented antigen were able to trigger IFNg-primed macrophages to produce nitric oxide by both CD40L-dependent and CD40L-independent signaling pathways.

Document Type

Dissertation - Campus Only

Copyright

Copyright by the authors.

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