Gap Junctions at the Dendritic Cell-T Cell Interface Are Key Elements for Antigen-Dependent T Cell Activation

Abstract

The acquired immune response begins with Ag presentation by dendritic cells (DCs) to naive T cells in a heterocellular cell-cell contact-dependent process. Although both DCs and T cells are known to express connexin43, a gap junction protein subunit, the role of connexin43 on the initiation of T cell responses remains to be elucidated. In the present work, we report the formation of gap junctions between DCs and T cells and their role on T cell activation during Ag presentation by DCs. In cocultures of DCs and T cells, Lucifer yellow microinjected into DCs is transferred to adjacent transgenic CD4+ T cells, only if the specific antigenic peptide was present at least during the first 24 h of cocultures. This dye transfer was sensitive to gap junction blockers, such as oleamide, and small peptides containing the extracellular loop sequences of conexin. Furthermore, in this system, gap junction blockers drastically reduced T cell activation as reflected by lower proliferation, CD69 expression, and IL-2 secretion. This lower T cell activation produced by gap junction blockers was not due to a lower expression of CD80, CD86, CD40, and MHC-II on DCs. Furthermore, gap junction blocker did not affect polyclonal activation of T cell induced with anti-CD3 plus anti-CD28 Abs in the absence of DCs. These results strongly suggest that functional gap junctions assemble at the interface between DCs and T cells during Ag presentation and that they play an essential role in T cell activation.

Gap Junction Intercellular Communications Regulate NK Cell Activation and Modulate NK Cytotoxic Capacity

“…The essential role of Cxs and GJs regulating key immunological processes has become increasingly clear in recent years (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Although Cx43 expression in NK cells was first described over a decade ago (6), the role of Cx43 in NK cell function and activation remains largely unknown.…”

“…Cx43 expression has been described in different types of immune system cells, including neutrophils, dendritic cells (DCs), macrophages, NK cells, T cells, and B cells (5,6). Cxs and GJIC participate in key immunological processes, such as Ig secretion and cytokine production (7), transendothelial migration of leukocytes (8), peptide transfer and cross-presentation (9, 10), DC activation (11), regulatory T cell-mediated suppression through the transfer of cAMP (12), DC-mediated induction of IL-2 release, and proliferation of murine T cells (13). Recently, we showed that Cx43 accumulates at the immunological synapse (IS) during Ag-specific CD4 + T cell priming, mediating bidirectional crosstalk between DCs and T cells.…”

Connexins and pannexins in the immune system and lymphatic organs

“…cells crossed with Cx43 floxed mice, Kuczma and group set out to study the effect of Cx43 deletion in this lymphocyte population [47]. In contrast to the reports by Elgueta and team and Oviedo-Orta and colleagues [44,46] [44,46], no differences in CD4 ? effector T-cell proliferation were observed between wild-type lymphocytes and those lacking Cx43 using this model system [47].…”

“…Using a TCR transgenic mouse model, dye coupling was detected between dye-loaded DCs and CD4 ? T-cells in vitro [44]. Dye coupling was detectable by 4 h of co-culture, reached a maximum at 8 h, and could be abolished by treatment with oleamide or a Cx43 mimetic peptide.…”

“…Interestingly, this anti-proliferative effect was limited to T-cell/DC co-cultures, as activation of T-cells with anti-CD3/anti-CD28 was not impacted by the presence of inhibitors, implying a role for Cx43 in the immune synapse. Although this report examined the effect of oleamide on expression of various components of the immune synapse, such as MHC class II, CD80, CD86 and CD40, their functionality was not addressed, a potential complication owing to the known pharmacological promiscuity of oleamide [44]. A second report placing Cx43 at the immune synapse was provided by MendozaNaranjo and team [45].…”