Molecular mechanisms of T cell receptor dysfunction induced by human immunodeficiency virus type 1 envelope protein.

Format:

Book

Thesis/Dissertation

Author/Creator:

Maitland, Anne Lydia.

Contributor:

Gaulton, Glen N., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Immunology.

Molecular biology.

0307.

0982.

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

0307.

0982.

Physical Description:

181 pages

Contained In:

Dissertation Abstracts International 59-11B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Acquired Immunodeficiency Syndrome (AIDS) is characterized by severe immunodeficiency and lymphopenia, with dramatic loss of CD4+ T cells. Yet prior to the destruction of this population, CD4+ T cells isolated from asymptomatic Human Immunodeficiency Virus-type 1 (HIV-1) seropositive individuals exhibit diminished proliferative responses and function when challenged by nominal antigen or mitogen. CD4+ T cell dysfunction cannot be solely attributed to the effects of direct viral infection, since less that one percent of circulating T cells appear to be productively infected. Thus, efforts have focused on examining the effect of virus and host derived protein products on uninfected T lymphocytes. The envelope glycoprotein, gp120, is an attractive candidate, given its high affinity for CD4 and the role CD4 plays in T cell activation. In addition to sterically hindering cognate antigen recognition, HIV-1 gp120-binding has been shown to directly modify TCR mediated activation events. The studies presented here examined the role of CD4 and the chemokine receptor C-X-C R4 in gp120 induced TCR dysfunction. This data suggests that gp120 primarily mediates its effect through the coreceptor CD4. Using protein tyrosine kinase inhibitors and T cell lines that lack lckp56 kinase activity or protein, the contribution of abberrant CD4 coreceptor to TCR dysfunction was elaborated. Separate ligation of CD4, distinct from the TCR/CD3 complex, resulted in the functional inactivation of lckp56 and the upregulation of receptors, which rendered the affected T cell more susceptible to the induction of apoptosis and anergy. Gp120 induced TCR dysfunction was dependent of tyrosine phosphorylation, specifically, the activity of lck p56. Gp120 binding reduces the access of TCR/CD3 and CD4 to functional lckp56, which couples the antigen receptor complex to signaling pathways, leading to the development of effector functions. Yet the lck p56 protein remains available for participation in other TCR and CD4 mediated events, such as the upregulation of receptors, which can influence TCR function, as well as activation of apoptotic machinery.

Notes:

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 1998.

Source: Dissertation Abstracts International, Volume: 59-11, Section: B, page: 5773.

Adviser: Glen N. Gaulton.

Local Notes:

School code: 0175.

ISBN:

9780599121027

Access Restriction:

Restricted for use by site license.