Triggering of the T3-Ti antigen-receptor complex results in clonal T-cell proliferation through an interleukin 2-dependent autocrine pathway.

Abstract

Human T-cell clones and anti-T-cell-receptor antibodies (clonotypic) directed at surface receptors for antigen (T3-Ti molecular complex) as well as anti-interleukin 2 (IL-2) and anti-IL-2-receptor antibodies were utilized to investigate the mechanism by which alloantigens or antigen plus self-major histocompatibility complex (MHC) (i.e., physiologic ligand) trigger specific clonal proliferation. Soluble or Sepharose-bound anti-Ti monoclonal antibodies, like physiologic ligand, enhanced proliferative responses to purified IL-2 by inducing a 6-fold increase in surface IL-2 receptor expression. In contrast, only Sepharose-bound anti-Ti or physiologic ligand triggered endogenous clonal IL-2 production and resulted in subsequent proliferation. The latter was blocked by antibodies directed at either the IL-2 receptor or IL-2 itself. These results suggest that induction of IL-2 receptor expression but not IL-2 release occurs in the absence of T3-Ti receptor crosslinking. Perhaps more importantly, the findings demonstrate that antigen-induced proliferation is mediated through an autocrine pathway involving endogenous IL-2 production, release, and subsequent binding to IL-2 receptors.Recent studies using cloned antigen-specific T lymphocytes and monoclonal antibodies directed at their various surface glycoprotein components have led to identification of the human T-cell-antigen receptor as a surface complex comprised of a clonotypic 90-kilodalton (kDa) Ti heterodimer and the monomorphic 20/25-kDa T3 molecule (1, 2). Upon binding to the surface of a clone, monoclonal antibodies to either T3 or its associated unique Ti heterodimer induced rapid loss of the T3-Ti complex, a process termed modulation, and inhibited all antigen-specific functions of a given clone. However, at the same time, these antibodies produced a markedly enhanced clonal proliferative response to interleukin 2 (IL-2)-containing media (1-3). Moreover, when coupled to the surface of a solid support such as Sepharose, the appropriate surface-linked anti-Ti and anti-T3 antibodies were able to induce IL-2 secretion and clonal proliferation, analogous to physiologic ligand (i.e., antigen) itself (4). These findings suggested that clonal proliferation resulting from triggering of the T3-Ti antigen receptor might be mediated through the growth factor IL-2. The latter is a 15-kDa sialoglycoprotein that interacts with activated T cells through specific membrane receptors distinct from the T3-Ti complex and is known to induce T-cell growth upon surface binding (5-12).The present study was performed to examine the relationship between the T-cell-antigen receptor and IL-2-mediated T-cell growth. MATERIALS AND METHODSHuman T-Cell Clones. The human T-cell clones CT8111, CT411, and RW17C were obtained from a single donor's peripheral blood mononuclear cells, cloned, and maintained in culture as described (13,14). Briefly, the cytotoxic clones CT8111 and CT411 have a target specificity for class I and class II alloantigens, respectively, both of which are present...

Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.

“…The interaction of IL-2 with its receptor on T cells has been shown (19) to be of primary importance in T cell growth, and satisfies the criteria for an autocrine system. One of the consequences of this interaction is an upregulation in cellsurface membrane IL-2-R (20, 21).…”

A synaptic basis for T-lymphocyte activation

“…The final physiological effect depends directly on the number of receptors which are bound or occupied and then subsequently crosslinked. Low levels of cross-linking, usually with antibody alone as shown with anti-Thy-1, anti-T3 and anti-clonotypic antibodies, activates only IL-2 receptor expression, while higher levels are required for IL-2 production [4,13,14]. Regulation of activation can therefore be accomplished by controlling the amount of cross-linking.…”

“…Some of these molecules have autostimulatory capacities and, once secreted into the junction, would feed back to the producer T cell. IL-2 may function by this pathway [14].…”

Purification of Ag-Specific T Lymphocytes After Direct Peripheral Blood Mononuclear Cell Stimulation Followed by CD25 Selection. I. Application to CD4+ or CD8+ Cytomegalovirus Phosphoprotein pp65 Epitope Determination

“…In this report we describe a method that we considered initially for the following reasons: cross-linking of the Ag-specific receptor on the surface of T lymphocytes is the key signal for CD25 expression (11)(12)(13), and CD25 expression can occur even in the absence of APC (14). Consequently, we reasoned that if autologous presentation (B-T, monocyte-T, or T-T) of a particular epitope among fresh PBMC can induce CD25 expression, then even rare specific T cells could be sorted out from the total population *Institut National de la Santé et de la Recherche Médicale Unité 463, Nantes, France; and † Institut National de la Santé et de la Recherche Médicale Unité 395, Toulouse, France…”