The long-term goal of this research is to better understand MHC class II-restricted antigen presentation. Class II a/beta heterodimers associate intracellularly with a third polypeptide chain, the invariant chain, that affects class II maturation. A significant contribution by this lab during the past period of support was the generation of a novel mouse strain carrying a targeted mutation at the invariant chain locus and the description of its striking phenotype. Experiments proposed in this application aim to further analyze the ability of invariant chain to affect the structure of MHC class II molecules on the surface of diverse antigen-presenting cells in the intact animal. We plan to compare the invariant chain dependency of class II molecules produced in different MHC backgrounds and to evaluate possible effect(s) of IL4/LPS stimulation on class II maturation. We will also examine biosynthesis and maturation of class II molecules expressed by dendritic cells, activated macrophages, and thymic stromal cells. A second goal is to further analyze the contribution of MHC-associated Ii chain to CD4+ T cell maturation. We plan to test the possibility that the few remaining CD4 T cells present in Ii mice may represent an intermediate, partially selected CD4 subset. We will examine their V/beta repertoire, and determine if these cells are triggered to proliferate and/or produce lymphokines in response to TCR crosslinking. Additionally, thymic organ cultures will be used to study defective CD4+ T cell maturation. We will seek evidence for positive selection by peptide and evaluate the V/beta repertoire of emerging CD4+ T cell clones. Finally, a major goal is to examine potentially divergent role(s) played by structurally distinct Ii31 and 41 proteins that arise as the result of alternative mRNA splicing. We plan to generate transgenic mouse strains that exclusively express the p31 or p41 form of invariant chain protein that also show an appropriate tissue-specific pattern of expression in vivo. These novel mouse strains will be used to analyze the capacity of invariant chain p31 and/or p41 alone to affect class II biochemistry, APC activity, and T cell selection in these strains. Overall, these experiments will hopefully provide further insight into functional role(s) played by the MHC class II-associated Ii chain in immune regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI019047-13
Application #
2060854
Study Section
Immunobiology Study Section (IMB)
Project Start
1981-09-01
Project End
1998-12-31
Budget Start
1994-04-01
Budget End
1994-12-31
Support Year
13
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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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