Engagement of the TCR causes an early rise in [Ca 2+ ] i

Engagement of the TCR causes an early rise in [Ca2+]i

Tsien et al, 1982

Population response Single-cell response (FACS)

QuickTime™ and aYUV420 codec decompressor

are needed to see this picture.

Single-cell responses (imaging)

Negulescu et al, 1996

The [Ca2+]i rise is necessary for T cell activationI. Pharmacological evidence

Chung et al, 1994

The [Ca2+]i rise is necessary for T cell activationII. Genetic evidence

Le Diest et al, 1995

The [Ca2+]i rise (with PKC activation) is sufficient to induce TCR-responsive genes

Diehn et al, 2002

Duration and amplitude requirements for the Ca2+ signal

Negulescu et al, 1994

Dolmetsch et al, 1998

Imboden & Stobo, 1985

Generation of the Ca2+ signal by antigen recognitionI. IP3-induced Ca2+ release

Winslow et al, 2003IP3

IP3-induced Ca2+ release is highly cooperative

Jurkat cells IP3 receptors in planar lipid bilayer

Bezprozvanny et al, 1991

TCR engagement triggers “capacitative” (store-operated) Ca2+ entry in lymphocytes

Mason et al, 1991

Premack et al, 1994

Zweifach and Lewis, 1993

TCR engagement stimulates Ca2+ entry via the CRAC channel

CRAC channels are the sole Ca2+ entry pathway triggered through the TCR

Ionomycin + PdBU

mutagenize

Ca

dipA

Ca

JurkatNFAT/dipA

survival

X Fanger et al, 1995(Also see Partiseti et al, 1994; Feske et al, 2001)

References

Reviews:Lewis, R.S. 2001. Calcium signaling mechanisms in T lymphocytes. Ann. Rev. Immunol.

19:497-521.Parekh, A.B., and R. Penner. 1997. Store depletion and calcium influx. Physiol. Rev.

77:901-930.Winslow, M.M., J.R. Neilson, and G.R. Crabtree. 2003. Calcium signalling in

lymphocytes. Curr. Opin. Immunol. 15:299-307.

Original papers:Bezprozvanny, I., J. Watras, and B.E. Ehrlich. 1991. Bell-shaped calcium-response

curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulumof cerebellum. Nature. 351:751-754.

Chung, S.C., T.V. McDonald, and P. Gardner. 1994. Inhibition by SK&F 96365 of Ca2+

current, IL-2 production and activation in T lymphocytes. Br. J. Pharmacol.113:861-868.

Diehn, M., A.A. Alizadeh, O.J. Rando, C.L. Liu, K. Stankunas, D. Botstein, G.R.Crabtree, and P.O. Brown. 2002. Genomic expression programs and theintegration of the CD28 costimulatory signal in T cell activation. Proc. Natl.Acad. Sci. 99:11796-11801

Dolmetsch, R.E., K. Xu, and R.S. Lewis. 1998. Calcium oscillations increase theefficiency and specificity of gene expression. Nature. 392:933-936.

Fanger, C.M., M. Hoth, G.R. Crabtree, and R.S. Lewis. 1995. Characterization of T cellmutants with defects in capacitative calcium entry: genetic evidence for thephysiological roles of CRAC channels. J. Cell Biol. 131:655-667.

Imboden, J.B., and J.D. Stobo. 1985. Transmembrane signalling by the T cell antigenreceptor. Perturbation of the T3-antigen receptor complex generates inositolphosphates and releases calcium ions from intracellular stores. J. Exp. Med.161:446-456.

Le Deist, F., C. Hivroz, M. Partiseti, C. Thomas, H.A. Buc, M. Oleastro, B. Belohradsky,D. Choquet, and A. Fischer. 1995. A primary T-cell immunodeficiency associatedwith defective transmembrane calcium influx. Blood. 85:1053-1062.

Lewis, R.S., and M.D. Cahalan. 1989. Mitogen-induced oscillations of cytosolic Ca2+ andtransmembrane Ca2+ current in human leukemic T cells. Cell Regul. 1:99-112.

Mason, M.J., C. Garcia-Rodriguez, and S. Grinstein. 1991. Coupling betweenintracellular Ca2+ stores and the Ca2+ permeability of the plasma membrane.Comparison of the effects of thapsigargin, 2,5-di-(tert-butyl)-1,4-hydroquinone,and cyclopiazonic acid in rat thymic lymphocytes. J. Biol. Chem. 266:20856-20862.

Negulescu, P.A., T.B. Krasieva, A. Khan, H.H. Kerschbaum, and M.D. Cahalan. 1996.Polarity of T cell shape, motility, and sensitivity to antigen. Immunity. 4:421-430.

Negulescu, P.A., N. Shastri, and M.D. Cahalan. 1994. Intracellular calcium dependenceof gene expression in single T lymphocytes. Proc. Natl. Acad. Sci. USA. 91:2873-2877.

Partiseti, M., F. Le Deist, C. Hivroz, A. Fischer, H. Korn, and D. Choquet. 1994. Thecalcium current activated by T cell receptor and store depletion in humanlymphocytes is absent in a primary immunodeficiency. J. Biol. Chem. 269:32327-32335.

Premack, B.A., T.V. McDonald, and P. Gardner. 1994. Activation of Ca2+ current inJurkat T cells following the depletion of Ca2+ stores by microsomal Ca2+-ATPaseinhibitors. J. Immunol. 152:5226-5240.

Rabinovitch, P.S ., C.H. June, A. Grossmann, and J.A. Ledbetter. 1986. Heterogeneityamong T cells in intracellular free calcium responses after mitogen stimulationwith PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence withflow cytometry. J. Immunol. 137:952-961.

Tsien, R.Y., T. Pozzan, and T.J. Rink. 1982. T-cell mitogens cause early changes incytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature. 295:68-71.

Zweifach, A., and R.S. Lewis. 1993. Mitogen-regulated Ca2+ current of T lymphocytes isactivated by depletion of intracellular Ca2+ stores. Proc. Natl. Acad. Sci. USA.90:6295-6299.