NYU Department of Pathology | T Cell Tolerance: A Role For Calcium Channels

T Cell Tolerance: A Role For Calcium Channels

Current Research from the Feske Lab

T cells play a prominent role in the host defense against infections and in tumor surveillance. On the flip side, T cells—when insufficiently educated in the thymus or activated in the wrong context in the periphery—can mistake self-proteins as foreign and become potent mediators of autoimmune diseases such as type I diabetes or multiple sclerosis.

Multiple specialized subsets of T cells exist: CD4⁺ helper T cells-including T_H1, T_H2 and T_H17 cells, CD8⁺ cytotoxic T cells and regulatory T cells, or T_regs. The latter help terminate immune responses and prevent activation of autoreactive T cells that managed to escape negative selection in the thymus. They thus contribute both to averting the negative effects of an overreaching inflammatory immune response and to maintaining immunological tolerance to self.

Despite their different functions, T cells from all subsets are activated following the engagement of the T cell receptor (TCR) by peptide-MHC on antigen presenting cells. Peptide binding to the TCR causes activation of multiple signaling pathways including release of Ca²⁺ ions stored in the endoplasmic reticulum (ER) resulting in (i) a transient rise in cytoplasmic Ca²⁺ concentrations and (ii) diminished ER Ca²⁺ concentration. This reduction in ER Ca²⁺ is the trigger for the opening of Ca²⁺release activated Ca²⁺ (CRAC) channels that promote what is known as store-operated Ca²⁺ entry. It is this Ca²⁺ influx from outside the cell that is necessary for sustained T cell activation.

Recently the genes for the sensor of ER Ca²⁺ concentration and activator of Ca²⁺ channels and the long elusive CRAC channel itself have been cloned. Stromal interaction molecule 1 (STIM1) and ORAI1, respectively, are both necessary—and by many accounts in the literature sufficient—for store-operated Ca²⁺ influx. ORAI1 is a pore-forming subunit of the CRAC channel and when rendered non-functional by mutations in human patients causes a severe, life-threatening T cell immunodeficiency.

The effects of combined ablation of STIM1 and its paralog STIM2 have now been investigated in collaboration between the Rao Lab and the Feske Lab at Harvard Medical School; Dr. Stefan Feske recently joined the NYU Department of Pathology. In a paper recently published in Nature Immunology they show that both STIM1 and STIM2 are necessary for T cell activation. T cells from mice lacking STIM1, STIM2 or both have substantially reduced Ca²⁺ influx and cytokine production. Surprisingly, overall T cell development is normal in the absence of measurable store-operated Ca²⁺ entry. By contrast, growth of regulatory T cells is severely impaired in mice lacking both STIM1 and STIM2, evidenced by significantly reduced numbers of T_regs in the thymus and secondary lymphoid organs. The paucity and impaired function of T_regs results in infiltration of leukocytes into many organs and autoimmunity in these mice. This and parallel studies on the role of ORAI1 function in human and mouse T cells—now continued in the Feske Lab at NYU Medical Center—show the importance of store-operated Ca²⁺ entry in T cells in vivo and yield some surprising insights as to which aspects of immunity are particularly dependent on this pathway.