Dihydropyridine Receptors Are Selective Markers of Th2 Cells and Can Be Targeted to Prevent Th2-Dependent Immunopathological Disorders

Abstract

Th1 cells that produce IFN-γ are essential in the elimination of intracellular pathogens, and Th2 cells that synthetize IL-4 control the eradication of helminths. However, highly polarized Th1 or Th2 responses may be harmful and even lethal. Thus, the development of strategies to selectively down-modulate Th1 or Th2 responses is of therapeutic importance. Herein, we demonstrate that dihydropyridine receptors (DHPR) are expressed on Th2 and not on Th1 murine cells. By using selective agonists and antagonists of DHPR, we show that DHPR are involved in TCR-dependent calcium response in Th2 cells as well as in IL-4, IL-5, and IL-10 synthesis. Nicardipine, an inhibitor of DHPR, is beneficial in experimental models of Th2-dependent pathologies in rats. It strongly inhibits the Th2-mediated autoimmune glomerulonephritis induced by injecting Brown Norway (BN) rats with heavy metals. This drug also prevents the chronic graft vs host reaction induced by injecting CD4+ T cells from BN rats into (LEW × BN)F1 hybrids. By contrast, treatment with nicardipine has no effect on the Th1-dependent experimental autoimmune encephalomyelitis triggered in LEW rats immunized with myelin. These data indicate that 1) DHPR are a selective marker of Th2 cells, 2) these calcium channels contribute to calcium signaling in Th2 cells, and 3) blockers of these channels are beneficial in the treatment of Th2-mediated pathologies.

Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis

“…The functional presence of Ca v 1 channels in T lymphocytes has been suggested previously (30)(31)(32)(33)(34)(35). Ca v 1.1 ␣1 subunits are critical for TCR-induced calcium entry into CD4 ϩ T cells, as suggested by our recent studies of Ca v 1 ␤4 Ϫ/Ϫ and Ahnak1 Ϫ/Ϫ mice (8,11).…”

The cGMP/Protein Kinase G Pathway Contributes to Dihydropyridine-sensitive Calcium Response and Cytokine Production in TH2 Lymphocytes

“…Several studies support that DHPR are involved in calcium responses of non-excitable cells, including B lymphocytes (21), NK cells (19), dendritic cells (20), naive T cells (24), Th2 cells (18,28), and epithelial cells (45,46). It has been shown that signaling through the B cell receptor was coupled to a guanylate cyclase/cGMP-dependent pathway that controlled DHPR-dependent calcium entry (21).…”

“…Here we have shown that in Th2 lymphocytes DHPR antagonization by nicardipine reduced cGMP-mediated calcium response, suggesting a role for DHPR in cGMP signaling. Although the structure of DHPR has not been completely elucidated in lymphocytes, DHPR had been related to the ␣1 calcium channel subunit in B cells (21) as well as in Th2 cells (18) and human T cells (24). In excitable cells, the NO/cGMP/PKG pathway is known to activate or repress DHPR-dependent calcium currents depending upon the cell type (47,48).…”

“…Because we have recently shown that Th2 cells expressed DHPR (18), we investigated the role of cGMP in TCR-induced DHP-sensitive calcium response in these cells. DO11.10 cells were differentiated along the Th2 pathway by three weekly stimulations with antigen-presenting cells loaded with the OVA 323-339 peptide in the presence of IL-4 ϩ antiinterferon ␥ antibody (18). TCR stimulation for 2 (not shown) or 5 min (Fig.…”

“…Only low calcium concentration increase was measured in activated Th2 lymphocytes (3)(4)(5)(15)(16)(17), suggesting an original [Ca 2ϩ ] i regulation mechanism in Th2 lymphocytes. We have previously shown that in Th2 cells TCR engagement involved dihydropyridine receptor (DHPR)-dependent calcium inflow (18). DHPR were also detected in other immune cells including natural killer (NK) cells (19), dendritic cells (20), B lymphocytes (21,22), and naive T cells (23,24).…”