Activation/inactivation of CD4+ T cells in context of the Quorum Hypothesis

Abstract

Understanding how immunological tolerance is established has been the subject of intense investigation and several models have been put forward to define the circumstances under which antigens activate or inactivate lymphocytes. According to the commonly held Danger Model, a single CD4+ T cell can be activated by an antigen presenting cell (APC) under appropriately "dangerous" conditions that instruct the APC to upregulate its expression of co-stimulatory molecules necessary for CD4+ T cell activation. In the absence of danger signals, CD4+ T cell inactivation ensues. Conversely, the Quorum Hypothesis postulates that the antigen-dependent, B cell-mediated cooperation between a minimum number of antigen-specific CD4+ T cells leads to their activation, whereas too few antigen-specific CD4+ T cells would be inactivated by antigen. Using enzyme-linked immunospot assay and flow cytometry, we investigated whether the activation of murine T cell receptor transgenic CD4+ T cells in vitro was quorum-dependent. The number of cultured CD4+ T cells was critical to their ability to generate IL-2 and/or interferon gamma (IFN-𝛾) producing cells. In general, relatively low numbers of CD4+ T cells did not generate cytokine-producing cells, medium numbers generated IL-2-producing cells, while higher numbers generated IL-2 and IFN-𝛾-producing cells. This quorum effect in the generation of cytokine-producing cells was not mediated by a difference in the proliferation of CD4+ T cells cultured under different conditions. Importantly, CD4+ T cells generated cytokine-producing cells without the deliberate use of Danger molecules, leading to the suggestion that Danger signals were not critical for CD4+ T cell activation. Moreover, our observations suggest that quorum sensing is mediated by a linked mechanism. CD4+ T cells specific for a non-crossreacting antigen optimally facilitated the activation of CD4+ T cells specific for the target antigen only if the two antigens were presented by the same APC. Lastly, our preliminary observations support a difference in the role of dendritic cells and B cells in mediating quorum sensing. In conclusion, our observations are consistent with the predictions of the Quorum Hypothesis. Further investigation is required to determine if CD4+ T cells are inactivated by antigen if cultured at limiting densities.