Previous studies have shown that central memory T (TCM) cells predominantly use the calcium-dependent potassium channel KCa3.1 during acute activation, whereas effector memory T (TEM) cells use the voltage-gated potassium channel Kv1.3. Because Kv1.3-specific pharmacological blockade selectively inhibited anti-CD3-mediated proliferation, whereas naive T cells and TCM cells escaped inhibition due to up-regulation of KCa3.1, this difference indicated a potential for selective targeting of the TEM population. We examined the effects of pharmacological Kv1.3 blockers and a dominant-negative Kv1.x construct on T cell subsets to assess the specific effects of Kv1.3 blockade. Our studies indicated both TCM and TEM CD4+ T cells stimulated with anti-CD3 were inhibited by charybdotoxin, which can block both KCa3.1 and Kv1.3, whereas margatoxin and Stichodactyla helianthus toxin, which are more selective Kv1.3 inhibitors, inhibited proliferation and IFN-γ production only in the TEM subset. The addition of anti-CD28 enhanced proliferation of freshly isolated cells and rendered them refractory to S. helianthus, whereas chronically activated TEM cell lines appeared to be costimulation independent because Kv1.3 blockers effectively inhibited proliferation and IFN-γ regardless of second signal. Transduction of CD4+ T cells with dominant-negative Kv1.x led to a higher expression of CCR7+ TCM phenotype and a corresponding depletion of TEM. These data provide further support for Kv1.3 as a selective target of chronically activated TEM without compromising naive or TCM immune functions. Specific Kv1.3 blockers may be beneficial in autoimmune diseases such as multiple sclerosis in which TEM are found in the target organ.
ASJC Scopus subject areas
- Immunology and Allergy