Although the presence of GJCs at ultrastuctural level was shown at the end of the 80s during antigen presentation [38, 51, 52], immunologists put an eye on the GJC field after the demonstration of antigen transfer (linear peptides up to 1,800kDa) through GJCs in APCs .
The transference of second messengers associated with [Ca.sup.2+] signaling, such as [IP.sub.3], through GJCs was demonstrated several years ago [22, 49].
Interestingly, [NAD.sup.+] permeates GJCs [22, 69] and Cx HCs [22,70], and upon activation of [P2X.sub.7] receptors increase the opening of Panx1 HCs .
Description of functional GJCs in T cells occurred almost 4 decades ago [81, 82].
Importantly, transfer of cGAMP occurs through GJCs between Cx43 and Cx45 overexpressing cells .
Although GJCs in immune cells were described in the early 70s by Hulser and Peters who reported gap junctional communication between T cells [81,82], the study of Cxs in APCs had to wait until the end of the decade when expression of GJCs and gap junctional communication was shown in macrophages [88, 89].
In addition, intercellular transfer of rhodamine-dextran (RD, ~10kDa), which due to its high molecular weight cannot permeate through GJCs, was not observed (Figure S2a).
In addition, in other cellular systems, functional Cx46 HCs stimulate formation of GJCs .
However, Cx43 seems to be the main contributor involved in cytokine-induced gap junctional communication, because microglia from Cx[43.sup.del/del] mice do not express functional GJCs in response to TNF-[alpha]/IFN-[gamma] .
Furthermore, inhibition of HCs prevents the pro-inflammatory molecules-induced upregulation of GJCs.
Thus, it is suggested that rises in [[Ca.sup.2+].sub.i]; together with other downstream pathways contribute to up-regulate Cx43 levels and formation of HCs and GJCs as observed in other cell types [45, 67].
We also found that in addition to TNF-[alpha]/IFN-[gamma], extracellular ATP and IL-1[beta] also positively modulate the formation of GJCs in microglia.