Title

An investigation into the physiological function of CD4 in the activation of T lymphocytes

Date of Award

1993

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

First Committee Member

James S. Peacock, Committee Chair

Abstract

The role of CD4 in the activation of T lymphocytes was investigated. The major difficulty in delineating the function of CD4 in T cell activation has been the inability to separate the transmembrane signaling aspect of this molecule from its role in promoting intercellular adhesion. In this study, the adhesion and transmembrane signaling roles of CD4 were examined using membrane-incorporated palmitoyl-proteins to stabilize cell-cell or cell-liposome interactions. Anti-CD4 antibody (Ab) was used to disengage the interaction of CD4 with MHC class II. The importance of CD4 was shown by the ability of this Ab to profoundly inhibit T cell activation induced by specific antigen (Ag) presented by Ag-presenting cells (APC). This anti-CD4-mediated inhibition was not overcome when T cell-APC conjugation was artificially maintained, demonstrating that CD4 functioned in T cell activation in a way other than contributing adhesion. These results suggested that by ligation of MHC class II, CD4 transduced signals involved in T cell activation. Ag-independent contact with APC caused an increase in intracellular (Ca$\sp{2+}$) and the tyrosyl phosphorylation of CD3 $\zeta$ in T cells. These responses were not abrogated by anti-CD4 treatment, demonstrating that the generation of these transmembrane signals was not dependent on CD4-MHC class II engagement. However, this did not exclude the possibility that MHC class II-ligation of CD4 can induce these signals. To investigate this possibility, liposomes bearing purified MHC class II were used to stimulate T cells. Contact with MHC class II-bearing liposomes did not cause an increase in T cell intracellular (Ca$\sp{2+}$), although it did induce tyrosine phosphorylation of CD3 $\zeta$ in these T cells. These results show that engagement of CD4 with its physiologic ligand, MHC class II, leads to CD3 $\zeta$ phosphorylation but not intracellular Ca$\sp{2+}$ mobilization.

Keywords

Biology, Cell; Health Sciences, Immunology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:9331524