Investigation of the role of the common gamma chain in early T cell development in a canine model of X-linked severe combined immunodeficiency / Terry A. Gouthro.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Gouthro, Terry A.

Contributor:

Felsburg, Peter J., advisor.

Henthorn, Paula S., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Pathology.

Pathology--Penn dissertations.

Pathology.

Academic Dissertations as Topic.

Medical Subjects:

Pathology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Pathology.

Pathology--Penn dissertations.

Physical Description:

xiii, 152 pages : illustrations, (some color) ; 29 cm

Production:

2002.

Summary:

T cell development is a coordinated process regulated by, among other things, signaling via cytokines and their receptors. Any given step in this development may be regulated by more than one cytokine and, conversely, any given cytokine may mediate several developmental steps. Cytokines, which signal via receptors having the common gamma chain (gammac) as an integral component, participate in the regulation of T cell development in this manner. X-linked severe combined immunodeficiency (XSCID), a genetic disease resulting from mutations in the gene for the common gamma chain, is characterized, in part, by defective T cell development. Dogs with XSCID have been shown to have a partial block in thymocyte development at the double negative (DN; CD4-CD8-) to double positive (DP; CD4+CD8+) transition. Determination of the timing of, and the critical mechanisms responsible for, this block should allow an understanding of the normal role of gammac-dependent signaling in thymocyte development. To identify the stage at which regulation of development of intrathymic T cells via gammac-dependent signaling first occurs, X-inactivation patterns were examined in subsets of thymic cells from XSCID carrier females. The role of the gammac in early thymocyte development was explored by examination and comparison of thymi from XSCID and age-matched normal dogs. Finally, to determine if environmental antigens have a role in gammac-dependent and gammac-independent thymocyte development, thymi from gnotobiotic normal and XSCID dogs were examined and compared with their conventionally-reared counterparts. Analysis of the results indicate that gammac-dependent signaling is functionally necessary for development of the DN subset of thymocytes thus supporting a role for gammac-mediated signaling in the proliferation and survival of thymic lymphocytes at the DN stage. The role of gammac-dependent signaling was shown to change with age. Additionally, environmental antigens were shown to play a part in gammac-independent pathways of thymocyte development. In conclusion, in the dog, signaling via gammac-dependent receptors has been demonstrated to coordinately regulate the development of DN thymocytes in a thymocyte stage-specific and animal age-specific manner yielding a model for the role of the gammacc that differs from the accepted murine model.

Notes:

Supervisors: Peter J. Felsburg; Paula S. Henthorn.

Thesis (Ph.D. in Pathology) -- University of Pennsylvania, 2002.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3073003.

OCLC:

244972119