Interference with Ca(2+) release activated Ca(2+) (CRAC) channel function delays T-cell arrest in vivo

Area of Science:

• Immunology
• Cell Biology
• Calcium Signaling

Background:

• Lymphocyte entry into secondary lymphoid organs (SLOs) requires intravascular arrest and calcium ion ([Ca(2+)]i) elevation.
• T-cell receptor (TCR) activation increases [Ca(2+)]i and arrests T-cell motility in vitro, but in vivo requirement is unknown.

Purpose of the Study:

• To investigate the role of calcium release-activated calcium (CRAC) channel pathway in T-cell homing, motility, and TCR signaling in vivo.
• To determine if [Ca(2+)]i elevation is required for T-cell arrest in secondary lymphoid organs.

Main Methods:

• Genetic deletion of stromal interaction molecule (STIM) 1 to disrupt CRAC channel function.
• Expression of a dominant-negative ORAI1 channel subunit (ORAI1-DN) in T cells.
• In vivo tracking of T-cell homing and motility following antigen stimulation.

Main Results:

• Absence of CRAC channels did not impede naive CD4(+) T-cell homing to SLOs or significantly reduce in vivo crawling speeds.
• T cells with ORAI1-DN lacked TCR-induced [Ca(2+)]i elevation but showed similar in vitro motility arrest.
• Antigen-specific ORAI1-DN T cells exhibited a twofold delay in motility arrest after peptide injection in vivo.

Conclusions:

• CRAC channel function is dispensable for T-cell homing to SLOs.
• CRAC channels enhance the spatiotemporal coordination of TCR signaling and T-cell motility arrest in vivo.
• Modulating CRAC channel activity impacts T-cell responses in secondary lymphoid organs.