Monocytes play a central role in the induction of immune responses, because of their capacity to generate signals required for T cell activation. CD14 is a 52 kD glycoprotein primarily expressed on mature monocytes. The function of CD14 is poorly understood. We have recently shown that monoclonal antibodies (mAb) to human CD14 induce a marked increase in monocyte adhesiveness. We have also strong evidence to suggest that CD14 is involved in adhesion between activated T cells and monocytes, and that engagement of CD14 results in inhibition of T cell proliferation. Taken together, these findings suggest that CD14 plays a regulatory role in monocyte-T cell interactions, which is mediated by binding of CD14 to a putative natural ligand expressed on activated T cells. We wish to study the role of CD14 in the human immune response. We propose to: I. Study the role of CD14 in the regulation of T cell activation, by assessing: (i) the mechanisms by which anti-CD14 mAb inhibit T cell proliferation; (ii) the CD14 epitopes responsible for inhibition, and (iii) heterogeneity of T cell sensitivity to inhibition via CD14. II. Clone the ligand for CD14 expressed on activated T cells. CD14- mediated adhesion systems will be established and used to enrich and screen a cDNA library obtained from activated human T cells. DNA probes and mAbs specific for the CD14 ligand will be generated. Expression cloning will be our first choice strategy; however, alternative approaches will also be considered. III. Characterize the ligand for CD14, using specific mAbs and DNA probes developed in the studies described in section II. We will study: (i) the biochemical characteristics; (ii) the cellular distribution; (iii) the induction of expression, and (iv) the role of the CD14 ligand on T cells. The elucidation of the interactions between CD14 and its ligand will result in a better understanding of monocyte-dependent regulation of T cell responses, and will lead to the development of novel strategies to interrupt T cell activation in disease states.
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| Cosentino, G; Soprana, E; Thienes, C P et al. (1995) IL-13 down-regulates CD14 expression and TNF-alpha secretion in normal human monocytes. J Immunol 155:3145-51 |
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