: The nature of peptides that positively select T cells in the thymus remains poorly defined. To examine the role of peptides during positive selection in vivo, we generated transpenic mice expressing class II restricted TCR specific for analogs of a pigeon cytochrome C peptide PCC(43-58) presented by the Ab molecule. The TCR transgenic mice were backcrossed to mice simultaneously lacking H2-M, invariant chain and TCRa-chain, where development of transpenic thymocytes is arrested at the CD4+CD8+ stage, due to the lack of the endogenously selecting peptide(s). However, injection of the soluble agonist peptide could restore positive selection of these thymocytes, making this model the first in vivo system of peptide induced positive selection of T cells. Hence, the specific aims of this proposal are as follow: 1: To determine biological properties of soluble peptides that can initiate positive selection of CD4+ T cells using this in vivo system. 2: To identify neutral peptides that positively select CD4+ T cells. 3: To analyze the activation and survival requirements of CD4+ T cells expressing one particular abTCR, positively selected in different in vivo environments. 4: To compare gene and protein expression profiles in thymocytes shortly following the onset of positive selection.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD036302-05A1
Application #
6543879
Study Section
Immunobiology Study Section (IMB)
Program Officer
Hewitt, Tyl
Project Start
1997-09-30
Project End
2007-05-31
Budget Start
2002-06-17
Budget End
2003-05-31
Support Year
5
Fiscal Year
2002
Total Cost
$258,300
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Ptaschinski, Catherine; Hrycaj, Steven M; Schaller, Matthew A et al. (2017) Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3. J Immunol 199:501-509
Demoor, Tine; Petersen, Bryan C; Morris, Susan et al. (2012) IPS-1 signaling has a nonredundant role in mediating antiviral responses and the clearance of respiratory syncytial virus. J Immunol 189:5942-53
Chmielowski, Bartosz; Pacholczyk, Rafal; Kraj, Piotr et al. (2002) Presentation of antagonist peptides to naive CD4+ T cells abrogates spatial reorganization of class II MHC peptide complexes on the surface of dendritic cells. Proc Natl Acad Sci U S A 99:15012-7
Kraj, P; Pacholczyk, R; Ignatowicz, H et al. (2001) Positive selection of CD4(+) T cells is induced in vivo by agonist and inhibited by antagonist peptides. J Exp Med 194:407-16
Kraj, P; Pacholczyk, R; Ignatowicz, L (2001) Alpha beta TCRs differ in the degree of their specificity for the positively selecting MHC/peptide ligand. J Immunol 166:2251-9
Gaszewska-Mastalarz, A; Muranski, P; Chmielowski, B et al. (2000) Altered selection of CD4+ T cells by class II MHC bound with dominant and low abundance self-peptides. J Immunol 165:6099-106
Muranski, P; Chmielowski, B; Ignatowicz, L (2000) Mature CD4+ T cells perceive a positively selecting class II MHC/peptide complex in the periphery. J Immunol 164:3087-94