Regulation of autoreactive MHC class II-restricted T cells by deletional and nondeletional mechanisms.

Format:

Book

Thesis/Dissertation

Author/Creator:

Jordan, Martha Susan.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Immunology.

0982.

Local Subjects:

0982.

Physical Description:

168 pages

Contained In:

Dissertation Abstracts International 61-10B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

To examine mechanisms by which CD4+ T cell tolerance is established to self-peptides, we analyzed separate lineages of transgenic mice (HA12 and HA28) that express hemagglutinin as a neo-self-antigen. These mice were mated with TS1 mice whose transgene encoded T cell receptors (TCRs) are specific for the major I-Ed-restricted determinant of HA, site 1 (S1). Most S1-specific CD4+ T cells in TS1 x HA12 mice are deleted in the thymus. Surprisingly, S1-specific CD4+ T cells were not substantially deleted in TS1 x HA28 mice; in fact, lymph node cells expressing high levels of the S1-specific TCRs were as abundant in TS1 x HA28 mice as in TS1 mice that lack the neo-self S1 peptide. Despite the presence of large numbers of S1-specific T cells, LN cells from TS1 x HA28 mice were impaired in their ability to proliferate in response to the S1 peptide both in vitro and in vivo. Impaired proliferation resulted from the presence of two distinct S1-specific T cell populations. Approximately half of the S1-specific CD4+ T cells in TS1 x HA28 mice expressed a unique cell surface phenotype (CD25+ CD45RBlow) and exhibited anergic and suppressor T cell properties; this population was hypo-proliferative and suppressed the proliferative capacity of co-existing S1-specific CD25 - CD45RBhi cells. Thymic selection of CD4 + CD25+ T cells in TS1 x HA28 mice was shown to be dependent upon recognition of the S1 agonist self-peptide as a high affinity ligand. The data herein demonstrate that agonist self-peptides can induce the development of anergic/suppressor T cells and that a single self-peptide can mediate both the selection and suppressor function of CD4+ CD25+ T cells. We further demonstrate that a single TCR specificity can be regulated by deletional or nondeletional mechanisms that are mediated by radioresistant thymic elements and that the outcome of selection is dependent upon the dose of S1 and/or the particular epithelial cell type responsible for its presentation.

Notes:

Source: Dissertation Abstracts International, Volume: 61-10, Section: B, page: 5226.

Supervisor: Andrew J. Caton.

Thesis (Ph.D.)--University of Pennsylvania, 2000.

Local Notes:

School code: 0175.

ISBN:

9780599969988

Access Restriction:

Restricted for use by site license.