Essential roles for Cavβ2 and Cav1 channels in thymocyte development and T cell homeostasis.
Calcium ions (Ca(2+)) are important in numerous signal transduction processes, including the development and differentiation of T cells in the thymus. We report that thymocytes have multiple types of pore-forming α subunits and regulatory β subunits that constitute voltage-gated Ca(2+) (Cav) channels. In mice, T cell-specific deletion of the gene encoding the β2 regulatory subunit of Cav channels (Cacnb2) reduced the abundances of the channels Cav1.2 and Cav1.3 (both of which contain pore-forming α1 subunits) and impaired T cell development, which led to a substantial decrease in the numbers of thymocytes and peripheral T cells. Similar to the effect of Cacnb2 deficiency, pharmacological blockade of pore-forming Cav1α subunits reduced the sustained Ca(2+) influx in thymocytes upon stimulation of the T cell receptor, decreased the abundance of the transcription factor NFATc3, inhibited the proliferation of thymocytes in vitro, and led to lymphopenia in mice. Together, our data suggest that Cav1 channels are conduits for the sustained Ca(2+) influx that is required for the development of T cells.
Trudeau Institute, Saranac Lake, NY 12983, USA.
Archana
A
Jha
Trudeau Institute, Saranac Lake, NY 12983, USA.
Ashish K
AK
Singh
Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany.
Petra
P
Weissgerber
Department of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Marc
M
Freichel
Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany.
Veit
V
Flockerzi
Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Richard A
RA
Flavell
Trudeau Institute, Saranac Lake, NY 12983, USA. mkjha98@gmail.com.
Mithilesh K
MK
Jha
D015220:Calcium Channels / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
D015220:Calcium Channels