The broad objective of this research is to investigate T cell responses to self and nonself immunoglobulins. The fact that IgG2a antigens are naturally expressed in Ia B lymphoma cells known to be fully capable of antigen presentation and that the structure of the antigen is readily manipulated using recombinant DNA techniques gives this system unique advantages for studying possible relationships between complex intracellular trafficking pathways and MHC restriction specificity. We plan to construct pSV2gt vectors encoding various forms of the C57BL/6 IgG2ab CH3. We are particularly interested in this portion of the molecule because allotypic determinants recognized by Igh-1b-specific T cell are located in the CH3 domain. Soluble, membrane-bound,and cytoplasmic form(s) of the C57BL/6 IgG2ab CH3 will be expressed in transfected B lymphoma cell lines. We will characterize the protein products that are synthesized and test whether these molecules are presented to Class II-restricted T cells. A major goal is to determine whether endogenously synthesized IgG2a antigens become associated with Class II molecules intracellularly. We will also express the VMPC11 -C57BL/6 IgG2ab CH3 protein under control of the human B- actin promoter in a variety of different types of Ia+ APC lines to test whether endogenous IgG2a synthesized by different types of Ia+ APC will stimulate Igh-1b-specific T cells. Overall, these experiments will hopefully lead to a clearer understanding of the possible role of antigen-presenting cells in MHC-restricted T cell recognition of self immunoglobulins and processes involved in T cell tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019047-08
Application #
3128486
Study Section
Immunobiology Study Section (IMB)
Project Start
1981-09-01
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Menges, Paula R; Jenks, Scott A; Bikoff, Elizabeth K et al. (2008) An MHC class II restriction bias in CD4 T cell responses toward I-A is altered to I-E in DM-deficient mice. J Immunol 180:1619-33
Koonce, Chad H; Bikoff, Elizabeth K (2004) Dissecting MHC class II export, B cell maturation, and DM stability defects in invariant chain mutant mice. J Immunol 173:3271-80
Ye, Qiang; Finn, Patricia W; Sweeney, Ruth et al. (2003) MHC class II-associated invariant chain isoforms regulate pulmonary immune responses. J Immunol 170:1473-80
Koonce, Chad H; Wutz, Gordana; Robertson, Elizabeth J et al. (2003) DM loss in k haplotype mice reveals isotype-specific chaperone requirements. J Immunol 170:3751-61
Fiebiger, Edda; Maehr, Rene; Villadangos, Jose et al. (2002) Invariant chain controls the activity of extracellular cathepsin L. J Exp Med 196:1263-9
Bikoff, E K; Wutz, G; Kenty, G A et al. (2001) Relaxed DM requirements during class II peptide loading and CD4+ T cell maturation in BALB/c mice. J Immunol 166:5087-98
Kenty, G; Bikoff, E K (1999) BALB/c invariant chain mutant mice display relatively efficient maturation of CD4+ T cells in the periphery and secondary proliferative responses elicited upon peptide challenge. J Immunol 163:232-41
Wright, R J; Bikoff, E K; Stockinger, B (1998) The Ii41 isoform of invariant chain mediates both positive and negative selection events in T-cell receptor transgenic mice. Immunology 95:309-13
Bikoff, E K; Kenty, G; Van Kaer, L (1998) Distinct peptide loading pathways for MHC class II molecules associated with alternative Ii chain isoforms. J Immunol 160:3101-10
Kenty, G; Martin, W D; Van Kaer, L et al. (1998) MHC class II expression in double mutant mice lacking invariant chain and DM functions. J Immunol 160:606-14

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