PubMed · 3155365
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J P Dessaint. IgE-dependent effector function in immune defence.. https://doi.org/10.1016/s0771-050x(86)80054-7
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The voltage gated potassium channel (Kv1.3) has been shown to play a role in immune responsiveness. Blockade of the channel led to diminution of T cell activation and delayed type hypersensitivity. Previous in vitro studies of the blockade were focused on T cell activation and proliferation. In this study we examined other T and monocytic cell mediated events to glean the extent of the immunosuppressive effects of a Kv1.3 specific inhibitor, Margatoxin (MgTX). We found that MgTX inhibited the intracellular production of Th-1 as well as Th-2 cytokines. MgTX can also inhibit IL-2 production and proliferation of T cells upon stimulation with anti-CD3 and VCAM-1. Furthermore, a redirected cytolytic activity was also inhibited by MgTX. However, MgTX did not inhibit generation of CTL to EBV transformed lymphoma cells or antibody-dependent cellular cytolysis mediated by monocytes. It appears that a Kv1.3 blockade does not affect all immune responses, particularly those of innate immunity.
2B4 (CD244) is a member of the CD2 subset of the immunoglobulin superfamily and functions as a triggering molecule on natural killer (NK) cells. Previously, we have found that 2B4-mediated activation of NK cells involves complex interactions involving LAT, Ras, Raf, ERK and p38 and that cytolytic function and cytokine production may be regulated by distinct pathways. Here we assessed the role of protein kinase C (PKC) in 2B4-mediated cytotoxicity of YT cells, a human NK cell line. Our data indicate that PKC-delta is activated upon stimulation with monoclonal antibody against 2B4. Treatment with the PKC inhibitor, bisindolylmaleimide I (Gö6850), of YT cells or YT cells depleted of Ca2+-dependent isoforms of PKC prior to 2B4 stimulation, resulted in inhibition of natural cytotoxicity and redirected antibody-dependent cellular cytotoxicity. However, inhibition of PKC failed to block 2B4 stimulation of interferon-gamma secretion as opposed to pretreatment with LY294002, a phosphoinositide 3-kinase inhibitor. We also examined the effect of phorbol 12-myristate 13-acetate (PMA) induction on 2B4 gene transcription. PMA induction resulted in a more than two-fold increase of 2B4 transcription. However, when we introduced a three-base substitution mutation to disrupt the activator protein-1 binding site at (-106 to -100) in the 2B4 promoter, we found complete loss of transcriptional activity, including the two-fold increase due to PMA induction of PKC. The present study indicated that PKC may play an important role in 2B4 signalling and activator protein-1 activation.
Identification of immune correlates associated with disease progression will provide information for HIV-1 vaccine design in countries such as Thailand, where the prevalent subtypes (B and CRF01_AE [E]) are characterized. In this study, plasma viral load and humoral immune responses were measured in 20 HIV-1 subtype E-infected Thai patients with different rates of disease progression, based on CD4(+) T cell decline and clinical symptoms. Nine progressors (PRs) and 11 slower progressors (SPs) were evaluated. CD4(+) T cell counts were inversely correlated with viral load (p = 0.004) and positively correlated with p24 Ab (p = 0.022). In progressors, p24 Ab showed a significant decrease (p < 0.001) over time. V3 and gp41 Ab did not change significantly in either group. Both CD4-binding site (CD4/gp120BS) and gp120 titers correlated positively with neutralizing antibody (NAb) against both a subtype E cell line-adapted virus (NP03) and a primary isolate (TH023). However, V3 Ab correlated only with NAb against NP03 (p < 0.001). Increased NAb over time was observed more frequently in SPs as compared with PRs, against both the TH023 (p = 0.004) and NPO3 (p = 0.004) viruses. Cross-clade antibody-dependent cellular cytotoxicity was demonstrated in both groups. These data suggest that in HIV-1 subtype E infection, declining p24 Ab titer is a predictive marker of disease progression, as described for subtype B. Furthermore, in subtype E-infected patients, slower progressors retain the immune competence to develop new antibody responses to Env over time; these evolving responses may contribute to prolonged survival during HIV-1 disease progression.