Newly Activated T Cells Promote Maturation of Bystander Dendritic Cells but Not IL-12 Production

Abstract

The activation of dendritic cells (DC) leads to increased costimulatory activity (termed DC maturation) and, in some instances, production of immunomodulatory cytokines such as IL-12. Both innate and T cell-derived signals can promote DC activation but it is unclear to what extent the two classes of stimuli are interchangeable or regulate distinct aspects of DC function. In this study, we show that signals from newly activated CD4+ T cells cannot initiate IL-12 synthesis although they can amplify secretion of bioactive IL-12 p70 by DC exposed to an appropriate innate stimulus. This occurs exclusively in cis and does not influence IL-12 synthesis by bystander DC that do not present Ag. In marked contrast, signals from newly activated CD4+ T cells can induce an increase in DC costimulatory activity in the absence of any innate priming. This occurs both in cis and in trans, affecting all DC in the microenvironment, including those that do not bear specific Ag. Consistent with the latter, we show that newly activated CD4+ T cells in vivo can deliver “help” in trans, effectively lowering the number of MHC/peptide complexes required for proliferation of third-party naive CD4+ T cells recognizing Ag on bystander DC. These results demonstrate that DC maturation and cytokine production are regulated distinctly by innate stimuli vs signals from CD4+ T cells and reveal a process of trans activation of DC without secretion of polarizing cytokines that takes place during T cell priming and may be involved in amplifying immune responses.

Activation of the Ancestral Polarity Regulator Protein Kinase Cζ at the Immunological Synapse Drives Polarization of Th Cell Secretory Machinery toward APCs

“…These observations reveal that dedicated Th cell polarization has indeed an impact on some but not all DC biological responses. These results extend previously published data showing that coculture of DCs with Th cells, gd T cells, or NK cells activates DCs to IL-12 production (24,25,34,35), whereas upregulation of costimulatory molecules by DCs can be triggered in the absence of direct T cell/DC contact (25,24).…”

“…3A), indicating that Th cell-driven DC upregulation of costimulatory molecules is uncoupled from Th cell polarization. In a second set of experiments, we investigated whether the inhibition of the PKCz pathway in T cells could inhibit IL-12 production by DCs, a function known to require the physical contact with Th cells (24,25). This analysis showed that DCs cultured with PKCz-PSpretreated Th cells released lower amounts of IL-12 when compared with DCs interacting with untreated T cells (Fig.…”

Reciprocal Polarization of T and B Cells at the Immunological Synapse

“…3). These results are in agreement with previously published data showing that the upregulation of surface activation markers by dendritic cells (DCs) requires neither dedicated Th cell polarization nor Th cell/DC contact (27)(28)(29).…”

T Cell Polarity at the Immunological Synapse Is Required for CD154-Dependent IL-12 Secretion by Dendritic Cells

“…Moreover, others and we have shown that the IS formation plays a key role in T/DC cross-talk (30,(35)(36)(37)(38). We thus examined the distribution of CD154 at the IS formed between human monocyte-derived DCs and autologous CD4…”