Three‐cell‐type clusters of T cells with antigen‐presenting cells best explain the epitope linkage and noncognate requirements of the in vivo cytolytic response

Abstract

Using an established i.p. adoptive transfer system in which primed precursors of cytolytic (Tc) cells are combined with primed helper (Th) cells and alloantigen, the three-cell-type hypothesis of T-T cooperation has been tested. This hypothesis assumes that cooperation takes place through the formation of clusters, consisting of one or more Tc precursors plus one or more Th cells binding to antigen on the surface of antigen-presenting cells (APC). By using antigens in which the H-2Db epitopes recognized by the Tc precursors are presented either on the same cell as the BALB minor histocompatibility epitopes recognized by the Th cells, or a different one, the value of epitope-linkage has been explored. Epitope-linkage is found to enhance the response at low concentrations of antigen but not at high ones, in accordance with the prediction that at low concentrations individual APC will usually take up either one antigen or the other but not both from an unlinked mixture, while at high concentrations most APC will take up both whether they are linked or not. In a further test of this hypothesis, no requirement for a cognate T-T interaction could be detected. With the three-cell-type interaction thus better established, its implications in terms of efficiency compared with linked-cognate interactions and its evolution are discussed.

Three-Cell Interactions in T Cell-Mediated Suppression? A Mathematical Analysis of Its Quantitative Implications

“…In this context, suppression dependent on simultaneous conjugation of regulatory and target T cells with the APC is an obvious testable candidate due to inherent probabilistic constraints. Mechanisms of interaction involving the formation of conjugates of more than two cell types have been postulated previously (31), the major example being the classical view of linked recognition of Ag aby CD4 and CD8 T cells and their cooperation. It has been argued (32,33) that such interaction imposes strong constraints on the efficiency of the process where it is imbedded due to the relatively low frequency of its rate-limiting event, the simultaneous encounter between more than two cells.…”

Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses

“…This IL-2 production is thought to be necessary for CTL activation. 12,13,17,18 In our study, we show that the PADRE-specific CD4 + T-cell line can be activated by PADRE-loaded DCs to release Th1 type of cytokines including IL-2 ( Figure 5). Furthermore, incubation of E7-specific CD8 + T cells with activated PADRE-specific CD4 + T cells stimulated by PADRE-loaded DCs led to the proliferation of E7-specific CD8 + T cells and this proliferation was abolished by incubation with an IL-2-blocking antibody ( Figure 6).…”

“…Several models have been proposed to illustrate this role of CD4 + T cells in enhancing the antigen-specific CD8 + T-cell immune responses. [12][13][14][15][16] Among these models, the 'three-cell interaction' model, which proposes that antigen-presenting cells (APCs) deliver co-stimulatory signals to the CD4 + T helper cells, which in turn generate IL-2. This IL-2 production is thought to be necessary for CTL activation.…”

Enhancing DNA Vaccine Potency by Combining a Strategy to Prolong Dendritic Cell Life and Intracellular Targeting Strategies with a Strategy to Boost CD4+ T Cells

“…In one model, APCs deliver costimulatory signals to the CD4 + helper T cells, which in turn generate interleukin-2. This interleukin-2 production is important for the activation of antigen-specific CD8 + T cells (Mitchison and O'Malley, 1987;Bennett et al, 1997;Xiang et al, 2005). Another model proposes that the contact of CD4 + T cells with APCs leads to the maturation of APCs, which subsequently leads to activation of CD8 + T cells (Bousso and Robey, 2003;Bevan, 2004;Xiang et al, 2005).…”