This proposal examines the signalling abnormalities in lpr immature T lymphocytes in order to understand the apparent developmental arrest and refractory state of the accumulating CD3+ CD4-CD8- T cells, and its parallels with normal T cell tolerance. It further studies the possible consequences of the signal defect on the regulation of surface CD4, CD8, and T cell antigen receptor (TCR) gamma/delta, as well as aberrant INFgamma, IL4, and TNFalpha lymphokine profiles produced by lpr immature versus mature T cells. These latter studies may be particularly relevant to the autoimmune process in these mice. The first specific aim completes a study of calcium and phosphoinositide flux in lpr CD4-8- T cells that show transmembrane signal events to be intact. It then uses the information of constitutive CD3 zeta tyrosine phosphorylation and delayed proliferative responses in lpr CD4-8- T cells to explore the temporal expression of two T cell tyrosine kinases, lck and fyn. Finally, the expression of IL2 gene nuclear regulatory proteins by lpr CD4-8- cells are used to further assess discrete signal pathway abnormalities.
The second aim examines methylation of the CD8 gene in lpr CD4-8- cells to assess the question of whether these cells underwent thymic selection at a CD4+8+ stage. It will also explore whether the markedly increased levels of TCR gamma and delta mRNA in cultured lpr CD4-8- cells are translated to gamma/delta protein.
The third aim examines aberrantly low lymphokine production by lpr immature T cells, in particular, the absence of INFgamma protein despite the presence of INFgamma mRNA. It also explores the aberrantly high levels of INFgamma and possibly IL4 by lpr mature T cells and normal (Pgp-1+) memory T lymphocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI028892-01A1
Application #
3455379
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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