Ion Channels, Calcium Signaling, T Lymphocytes, Imaging, Cell Motility and Interaction Dynamics
1970: Graduated Oberlin College Phi Beta Kappa, Magna cum laude
1976: Muscular Dystrophy Association Postdoctoral Fellowship
1981: NIH Research Career Development Award
1989-90: Alexander von Humboldt Senior Scientist Prize
1991-95, 2006-present: Department Chair
1997: Athalie Clark Research Achievement Award
1998: Elected President, Society of General Physiologists
2000: Kenneth S. Cole Award in Membrane Biophysics
2006-13: Javits Neuroscience Investigator Award
2008: Elected to the Henry Kunkel Society
2009,11,13: Excellence in Teaching Award from medical students
2010: Elected to the U.S. National Academy of Sciences
2011: UCI Distinguished Faculty Award for Research
postdoctoral research with Clay Armstrong, University of Pennsylvania, 1974-1977
Cahalan’s pioneering work identified the pivotal role of ion channels in the immune response. He elucidated physiological functions and the molecular basis for calcium signaling that activates T lymphocytes. By imaging in lymphoid organs, his work revealed an elegant cellular choreography that underlies immune responses in vivo.
We continue to develop and apply single-cell approaches to investigate the immune system. Our work in three inter-related areas is described below:
Ion channels in the immune system: functional network, therapeutic targets.
Our research group discovered the biophysical characteristics and molecular properties of a functional network of ion channels in T lymphocytes. Previously, ion channels were ordinarily thought of as mediating electrical signaling in the nervous system and the heart. Our group was the first to characterize ion channels in lymphocytes and the first to demonstrate a specific requirement for ion channel activity in T cell functions including: membrane potential, cell volume, calcium signaling, cellular motility, gene expression, and cell proliferation. Kv1.3 and Orai1 show promise in animal models and clinical trials as therapeutic targets for treatment of autoimmune diseases.
DeCoursey TE, Chandy KG, Gupta S, Cahalan MD. 1984. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature 307: 465-8. (cover illustration) PMID: 6320007
Chandy, K.G., T.E. DeCoursey, M.D. Cahalan, C. McLaughlin, S. Gupta. 1984. Voltage-gated potassium channels are required for human T lymphocyte activation. Journal of Experimental Medicine l60: 369-385. PMID: 6088661
Cahalan, M.D., K.G. Chandy, T.E. DeCoursey, and S. Gupta. 1985. A voltage-gated K+ channel in human T lymphocytes. J Physiol 358: 197-237. PMID: 2580081
DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1985. Voltage-dependent ion channels in T lymphocytes. Journal of Neuroimmunology 10: 71-85. PMID: 2414315
Chandy, K.G., T.E. DeCoursey, M. Fischbach, N. Talal, M.D. Cahalan, and S. Gupta. 1986. Altered K+ channel expression in abnormal T lymphocytes from mice with the lpr gene mutation. Science 233: 1197-1200. PMID: 2426784
DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1987. Two types of potassium channels in murine T lymphocytes. Journal of General Physiology 89: 379-404. PMID: 2435844
DeCoursey, T.E., K.G. Chandy, S. Gupta, and M.D. Cahalan. 1987. Mitogen induction of ion channels in murine T lymphocytes. Journal of General Physiology 89: 405-420. PMID: 2435845
Lewis, R.S. and M.D. Cahalan. 1988. Subset-specific expression of potassium channels in developing murine T lymphocytes. Science 239: 771-775. (cover illustration). PMID: 2448877
Cahalan, M.D. and R.S. Lewis. 1988. Role of potassium and chloride channels in volume regulation by T lymphocytes. Society of General Physiology Ser. 43: 282-301. PMID: 2479106
Grissmer, S., M.D. Cahalan, and K.G. Chandy. 1988. Abundant expression of type l K+ channels: a marker for lymphoproliferative diseases? Journal of Immunology 141: 1137-1142. PMID: 2456342.
Grissmer, S. and M.D. Cahalan. 1989. TEA prevents inactivation while blocking open K+ channels in human T lymphocytes. Biophysical Journal 55: 203-206. PMID: 2784693
Grissmer, S. and M.D. Cahalan. 1989. Divalent ion trapping inside potassium channels of human T lymphocytes. Journal of General Physiology 93: 609-630. PMID: 2786551
Sands, S.B., R.S. Lewis, and M.D. Cahalan. 1989. Charybdotoxin blocks voltage-gated K+ channels in human and murine T lymphocytes. Journal of General Physiology 93: 1061-1074. PMID: 2475579
Chandy, K.G., M.D. Cahalan, and S. Grissmer. 1990. Autoimmune diseases linked to abnormal K+ channel expression in double-negative CD4- CD8- T cells. European Journal of Immunology 20: 747-751. PMID: 1971790.
McCloskey, M.A. and M.D. Cahalan. 1990. G-protein control of potassium channel activity in a mast cell line. Journal of General Physiology 95: 205-227. PMID: 2106571
Grissmer, S., B. Dethlefs, J. Wasmuth, A.L. Goldin, G.A. Gutman, M.D. Cahalan, and K.G. Chandy. 1990. Expression and chromosomal localization of a lymphocyte K+ channel gene. Proceedings of the National Academy of Sciences U.S.A. 87: 9411-9415. PMID: 2251283
Grissmer, S., R.S. Lewis, and M.D. Cahalan. 1992. Ca2+-activated K+ channels in human leukemic T cells. J Gen Physiol 99: 1-23. PMID: 1371308
Grissmer, S., S. Ghanshani, B. Dethlefs, J. McPherson, J. Wasmuth, G. Gutman, M.D. Cahalan, and K.G. Chandy. 1992. The Shaw-related potassium-channel gene, Kv3.1, on human chromosome 11, encodes the type l K+ channel in T Cells. Journal of Biological Chemistry 267: 20971-20979. PMID: 1400413
Lewis, S., P. Ross, and M.D. Cahalan. 1993. Chloride channels activated by osmotic stress in T lymphocytes. Journal of General Physiology 101: 801-826. PMID: 7687269
Ross, P., S. Garber, and M.D. Cahalan. 1993. Membrane chloride conductance and capacitance in Jurkat T lymphocytes during osmotic swelling. Biophysical Journal 66: 169-178. PMID: 8130336
Grissmer, S., A.N. Nguyen, and M.D. Cahalan. 1993 Calcium-activated potassium channels in resting and activated human T lymphocytes. Journal of General Physiology 102: 601-630. PMID: 7505804
Ehring, G. R., Y.V. Osipchuk, and M.D Cahalan. 1994. Swelling-activated chloride channels in multidrug-sensitive and -resistant cells. Journal of General Physiology 104: 1129-1161. PMID: 7699367
Lewis, R.S. and M.D. Cahalan. 1995. Potassium and calcium channels in lymphocytes. Annual Review of Immunology 13: 623-653. PMID: 7612237
Verheugen, J.A.H., H.P.M. Vijverberg, M. Oortgiesen, and M.D. Cahalan. 1995. Voltage-gated and Ca2+ -activated K+ channels in intact human T lymphocytes. Journal of General Physiology 13: 765-794. PMID: 7561743
Lepple-Wienhues, and M.D. Cahalan. 1996. Conductance and permeation of monovalent ions through depletion-activated Ca2+ channels (Icrac) in Jurkat T cells. Biophysical Journal 71: 787-794. PMID: 8842217
Nguyen, A., J. Kath, D.C. Hanson, P.C. Kaniff, C. Donovan, R.J. Mather, M. Bruns, B. Dethlefs, H. Rauer, J. Aiyar, A. Lepple-Wienhues, G.A. Gutman, S. Grissmer, M.D. Cahalan, K.G. Chandy. 1996. Novel non-peptide agents block the C-type inactivated conformation of Kv1.3, and suppress T-cell activation. Molecular Pharmacology 50: 1672-1769. PMID: 8967992.
Garber, S.S. and M.D. Cahalan. 1997. Volume-regulated anion channels and the control of a simple cell behavior. Cellular Physiology and Biochemistry 7: 229-241
Cahalan, M.D. and K.G. Chandy. 1997. Ion channels in the immune system as targets for immunosuppression. Current Opinion in Biotechnology 8: 749-756. PMID: 9425667
Kalman, K., M.W. Pennington, M.D. Lanigan, A. Nguyen, H. Rauer, V. Mahnir, K. Paschetto, W.R. Kem, S. Grissmer, G.A. Gutman, E.P. Christian, M.D. Cahalan, R.S. Norton, and K.G. Chandy. 1998. ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide. Journal of Biological Chemistry 273: 32697-32707. PMID: 9830012
Kerschbaum, H.H. and M.D. Cahalan. 1998. Monovalent permeability, rectification, and ionic block of store-operated calcium channels in Jurkat T lymphocytes. Journal of General Physiology 111: 521-537. PMID: 9524136.
Ehring, G.E., H.H. Kerschbaum, C. Eder, A.L. Neben, C.M. Fanger, R.M. Khoury, P.A. Negulescu, and M.D. Cahalan. 1998. A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes. Journal of Experimental Medicine 188: 1593-1602. PMID: 9802971
Fanger, C.M., S. Ghanshani, N.J. Logsdon, H. Rauer, K. Kalman, J. Zhou, K. Beckingham, K.G. Chandy, M.D. Cahalan, and J. Aiyar. 1999. Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCA1. Journal of Biological Chemistry 274: 5746-5754. PMID: 10026195
Hanson, D.C., A. Nguyen, R.J. Mather, H. Rauer, K. Koch, L.E. Burgess, J.P. Rizzi, C.B. Donovan, M.J. Bruns, P.C. Canniff, A.C. Cunningham, K.A. Verdries, E. Mena, J.C. Kath, G.A. Gutman, M.D. Cahalan, S. Grissmer, K.G. Chandy. 1999. UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation. British Journal of Pharmacology 126:1707-1716. PMID: 10372812.
Rauer, H., M. Pennington, M.D. Cahalan, and K.G. Chandy. 1999. Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin. Journal of Biological Chemistry 274: 21885-21892. PMID: 10625664
Rauer, H., M.D. Lanigan, M.W. Pennington, J. Aiyar, S. Ghanshani, M.D. Cahalan, R.S. Norton, and K.G. Chandy. 2000. Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca2+-activated over voltage-gated K+ channels. Journal of Biological Chemistry 275: 1201-1208. (cover illustration). PMID: 10625664
Wulff, H., M.D. Cahalan, and K.G. Chandy. 2000. Design of a potent and selective inhibitor of the intermediate conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proceedings of the National Academy of Sciences U.S.A. 97: 8151-8156. PMID: 10884437
Ghanshani, S., H. Wulff, M.J. Miller, H. Rohm, A.L. Neben, G.A. Gutman, M.D. Cahalan, and K.G. Chandy. 2000. Up-regulation of the IKCa1 potassium channel during T-cell activation: molecular mechanism and functional consequences. Journal of Biological Chemistry 275: 37137-37149. PMID: 10961988
Wulff, H., G.A. Gutman, M.D. Cahalan, and K.G. Chandy. 2001. Delineation of the clotrimazole/TRAM-34 binding site on the intermediate conductance calcium-activated potassium channel, IKCa1. Journal of Biological Chemistry 276: 32040-32045. PMID: 11425865.
Beeton, C., H. Wulff, J. Barbaria, O. Clot-Faybesse, M. Pennington, D. Bernard, M.D. Cahalan, K.G. Chandy, and E. Beraud. 2001. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalitis, a model for multiple sclerosis. PNAS 98: 13942-13947. PMID: 11717451
Kozak, J.A., H.H. Kerschbaum, and M.D. Cahalan. 2002. Distinct properties of CRAC and MIC channels in RBL cells. Journal of General Physiology 120: 8601-8615. PMID: 12149283
Kozak, J.A. and M.D. Cahalan. 2003. MIC channels are inhibited by internal divalent cations but not ATP. Biophysical Journal 84: 922-927. PMID: 12547774
Chandy, K.G., H. Wulff, C. Beeton, M. Pennington, G.A. Gutman, M.D. Cahalan. 2004. K+ channels as targets for specific immunosuppression. Trends in Pharmacological Sciences 25: 280-289. PMID: 15120495
Matsushita, M., J.A. Kozak, Y. Shimizu, D. McLachlin, H. Yamaguchi, F.Y Wei, K. Tomizawa, H. Matsui, B. Chait, M.D. Cahalan, A.C. Nairn. 2005. Channel function is dissociated from the intrinsic kinase activity and autophosphorylation of TRPM7/CHAK1. Journal of Biological Chemistry 280: 20793-803. PMID: 15781465
Kozak, J.A., M. Matsushita, A.C. Nairn, and M.D. Cahalan. 2005. Charge screening by internal pH and polyvalent cations as a mechanism for activation, inhibition and rundown of TRPM7/MIC channels. Journal of General Physiology 126:499-514
Matheu, M.P., C. Beeton, A. Garcia, V. Chi, K. Monaghan, M.I. Uemura, D. Li, S. Pal, L.M. de la Maza, E. Monuki, A. Flugel, M.W. Pennington, I. Parker, K.G. Chandy, and M.D. Cahalan. 2008. Imaging of effector memory T cells during DTH and suppression by Kv1.3 channel block. Immunity 29: 602-614. PMID: 18835197
Cahalan MD, Chandy KG. 2009. The functional network of ion channels in T lymphocytes. Immunological Reviews 231: 59-87. PMID: 19754890
Calcium signaling: cellular functions, molecular machinery.
Calcium is a vital second messenger in all cells. Our group showed that cytosolic calcium in T cells regulates NFAT-mediated changes in gene expression, cytokine production, and cellular motility. We discovered the STIM and Orai proteins and showed that they embody the molecular machinery of store-operated calcium (CRAC) channel activity.
Lewis RS, Cahalan MD. 1989. Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regulation 1: 99-112. PMID: 2519622
Osipchuk, Y. and M. Cahalan. 1992. Cell-to-cell spread of calcium signals mediated by ATP receptors in a mast cell line. Nature 359: 241-244. PMID: 1388246
Hess, S., M. Oortgiesen, and M.D. Cahalan. 1993 Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx. Journal of Immunology 150: 2620-2633. PMID: 7681076
Negulescu, P., N. Shastri, and M.D. Cahalan. 1994. Intracellular calcium dependence of IL-2 gene expression in single T lymphocytes. PNAS 91: 2873-2877. PMID: 8146203
Ross, P.E. and M.D. Cahalan. 1995. Ca2+ influx pathways mediated by swelling and stores depletion in mouse thymocytes. Journal of General Physiology 106: 415-444. PMID: 8786341
Negulescu PA, Krasieva TB, Khan A, Kerschbaum HH, Cahalan MD. 1996. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4: 421-30. (cover illustration) PMID: 8630728
Kerschbaum, H.H., Negulescu, P.A. and M.D. Cahalan. 1997. Ion channels, [Ca2+]i signaling, and gene expression in an antigen-specific reporter T cell line. Journal of Immunology 159: 1628-1638. PMID: 9257822
Ross, P.E., G.R. Ehring, and M.D. Cahalan. 1997. Dynamics of ATP-induced calcium signaling in single mouse thymocytes. Journal of Cell Biology 138: 987-998. PMID: 9281578
Ehring, G.E., H.H. Kerschbaum, C. Eder, C.M. Fanger, H. Rauer, and M.D. Cahalan. 2000. Vanadate induces calcium signaling, Ca2+ release-activated Ca2+ channel activation, and gene expression in T lymphocytes and RBL-2H3 mast cells via thiol oxidation. Journal of Immunology 164: 679-687. PMID: 10623810.
Wei, X., B.J. Tromberg, and M.D. Cahalan. 1999. Mapping the sensitivity of T cells using an optical trap: polarity and minimal number of receptors for Ca2+ signaling. Proceedings of the National Academy of Sciences U.S.A. 96: 8471-8476. PMID: 10411899.
Fanger, C.M., A. Neben, and M.D. Cahalan. 2000. Differential Ca2+ influx, KCa channel activity and Ca2+ clearance distinguish Th1 and Th2 lymphocytes. Journal of Immunology 164: 1153-1160. PMID: 10640725
Wei, X., M-S. Si, D.K. Imagawa, P. Ji, B.J. Tromberg, and M.D. Cahalan. 2000. Perillyl alcohol inhibits TCR-mediated [Ca2+]i signaling, alters cell shape and motility, and induces apoptosis in T lymphocytes. Cellular Immunology 201: 6-13. PMID: 10805968.
Leissring, M.A., Y. Akbari, C.M. Fanger, M.D. Cahalan, M.P. Mattson, and F.M. LaFerla. 2000. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knock-in mice. Journal of Cell Biology 149: 793-797. PMID: 10811821
Fanger, C., H. Rauer, A.L. Neben, M.J. Miller, H. Rauer, H. Wulff, J.C. Rosa, C.R. Ganellin, K.G. Chandy, and M.D. Cahalan. 2001. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes; Selective blockers and manipulated expression levels. Journal of Biological Chemistry 276: 12249-12256. PMID: 11278890
Yeromin A.V., J. Roos, K.A. Stauderman, and M.D. Cahalan. 2004. A store-operated calcium channel in Drosophila S2 cells. Journal of General Physiology 123:167-182. PMID: 14744989
Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. 2005. STIM1, an essential and conserved component of store-operated Ca2+ channel function. Journal of Cell Biology 169: 435-45. PMID: 15866891
Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD. 2005. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437: 902-5. PMID: 16208375
Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD. 2006. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proceedings of the National Academy of Sciences U.S.A. 103: 9357-62. PMID: 16751269
Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. 2006. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443: 226-9. PMID: 16921385
Lioudyno, M.I., J.A. Kozak. A. Penna, O. Safrina, S.L. Zhang, D. Sen, J. Roos, K.A. Stauderman, and M.D. Cahalan. 2008. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. PNAS 105:2011-2016. PMID: 18250319
Penna, A., A. Demuro, A.V. Yeromin, S.L. Zhang, O. Safrina, I. Parker, and M.D. Cahalan. 2008. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456: 116-120. PMID: 18820677
Zhang, S.L., J.A. Kozak, W.Jiang, A.V. Yeromin, J. Chen, Y. Yu, A. Penna, W. Shen, V. Chi, and M.D. Cahalan. 2008. Store-dependent and -independent modes regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3. Journal of Biological Chemistry 283: 17662-17671. PMID: 18420579
Cahalan MD. 2009. STIMulating store-operated Ca2+ entry. Nature Cell Biology 11: 669-77. PMID: 19488056
Krummel, M.F. and M.D. Cahalan. 2010. The immunological synapse: a dynamic platform for local signaling. Journal of Clinical Immunology 30: 364-372. PMID: 20390326
Flach, H., M. Rosenbaum, M. Duchniewicz, S. Kim, S.L. Zhang, M.D. Cahalan, G. Mittler, and R. Grosschedl. 2010. Mzb1 protein regulates calcium homeostasis, antibody secretion, and integrin activation innate-like B cells. Immunity 33: 723-735. PMID: 21093319
Newton, R.H., S. Leverrier, S. Srikanth, Y. Gwack, M.D. Cahalan, and C.M. Walsh. 2011. Protein kinase D orchestrates the activation of DRAK2 in response to TCR-induced Ca2+ influx and mitochondrial reactive oxygen generation. Journal of Immunology 186: 940-950. PMID: 21148796
Demuro, A., A. Penna, O. Safrina, A.Y. Yeromin, A. Amcheslavsky, M.D. Cahalan, and I. Parker. 2011. Subunit stoichiometry of human Orai1 and Orai3 channels in closed and open states. Proceedings of the National Academy of Sciences U.S.A. 108: 17832-7. PMID: 21987805
Zhang, S.L., A.V. Yeromin, J. Hu, A. Amcheslavsky, H. Zheng, and M.D. Cahalan. 2011. Mutations in Orai1 TM1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proceedings of the National Academy of Sciences U.S.A. 108: 17838-43. PMID: 21987804
Greenberg, M.L., Y. Yu, S. Leverrier, S.L. Zhang, I. Parker, and M.D. Cahalan. 2013. Orai1 function is essential for T cell homing to lymph nodes. Journal of Immunology 190: 3197-3206. PMID 23455504
Amcheslavsky, A., O. Safrina, and M.D. Cahalan. 2013. Orai3 TM3 point mutation G158C alters kinetics of 2-APB-induced gating by disulfide bridge formation with TM2 C101. Journal of General Physiology 142: 405-412. PMID 24081982
Amcheslavsky, A., O. Safrina, and M.D. Cahalan. 2014. State-dependent block of Orai3 TM1 and TM3 cysteine mutants: insights into 2-APB activation. Journal of General Physiology 143: 621-631. PMID: 24733836
Amcheslavsky, A., M.L. Wood, A.V. Yeromin, I. Parker, J.A. Freites, D.J. Tobias, and M.D. Cahalan. 2015. Molecular biophysics of Orai store-operated Ca2+ channels. Biophysical Journal 108: 237-246. PMID: 25606672
Perni, S., J.L. Dynes, A.V. Yeromin, M.D. Cahalan, and C. Franzini-Armstrong. 2015. Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proceedings of the National Academy of Sciences U.S.A. 112(40): E25533-42. PMID: 26351694
Dynes JL, Amcheslavsky A, Cahalan MD. 2016. Genetically targeted single-channel optical recording reveals multiple Orai1 gating states and oscillations in calcium influx. Proc Natl Acad Sci U S A 113: 440-5. PMID: 26712003
Abud, E.M., R.N. Ramirez, E.S. Martinez, L.M. Healy, C.H.H. Nguyren, S.A. Newman, A.V. Yeromin, V.M. Scarfone, S.E. Marsh, C. Fimbres, C.A. Caraway, G.M. Fote, A.M. Madany, A. Agrawal, R. Kayed. K.H. Gylys, M.D. Cahalan, B.J. Cummings, J.P Antel, A. Mortazavi, M.J. Carson, W.W. Poon, M. Blurton-Jones. 2017. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94: 278-293. PMID: 28426964
Dong, T.X., S. Othy, M.L. Greenberg, A. Jairaman, C. Akunwafo, S. Leverrier, Y. Yu, I. Parker, J.L. Dynes, and M.D. Cahalan. 2017a. Intermittent Ca(2+) signals mediated by Orai1 regulate basal T cell motility. Elife. 6. PMID: 29239723
Dong, T.X., S. Othy, A. Jairaman, J. Skupsky, A. Zavala, I. Parker, J.L. Dynes, and M.D. Cahalan. 2017b. T-cell calcium dynamics visualized in a ratiometric tdTomato-GCaMP6f transgenic reporter mouse. Elife. 6. PMID: 29239725
Dynes JL, Yeromin AV, Cahalan MD. 2020. Cell-wide mapping of Orai1 channel activity reveals functional heterogeneity in STIM1-Orai1 puncta. Journal of General Physiology 152 (cover illustration). PMID: 32589186
Wakida, N.M., V. Gomez-Godinez, H. Li, J. Nguyen, E.K. Kim, J.L. Dynes, S. Othy, A.L. Lau, P. Ding, L. Shi, C. Carmona, L.M. Thompson, M.D. Cahalan, and M.W. Berns. 2020. Calcium Dynamics in Astrocytes During Cell Injury. Frontiers of Bioengineering and Biotechnology 8:912. PMID: 32984268
Cellular dynamics during immune responses.
Our group, working in collaboration with Ian Parker, pioneered the use of two-photon microscopy to image cell motility and interaction dynamics inside lymphoid organs. T and B cells are highly motile in their native habitat; “random walk” motility plays an important role in locating and responding to antigen. During the initiation of an immune response, T cells interact with and respond to dendritic cells forming clusters, whereas individual T cells pair up with individual B cells while delivering “help” to trigger antibody production. In vivo imaging approaches, in combination with targeted gene deletion and specific pharmacological agents, are continuing to revealing important insights into immune responses in health and disease.
Miller MJ, Wei SH, Parker I, Cahalan MD. 2002. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296: 1869-73. PMID: 12016203
Cahalan, M.D., I. Parker, S.H. Wei, and M.J. Miller. 2002. Two photon tissue imaging: seeing the immune response in a fresh light. Nature Reviews Immunology 2: 872-880. PMID: 12415310
Miller, M.M., S.H. Wei, I. Parker, and M.D. Cahalan. 2003. Autonomous T cell trafficking examined in vivo using intravital two-photon microscopy. Proceedings of the National Academy of Sciences U.S.A. 100: 2604-2609. PMID: 12601158
Miller, M.J., A.S. Hejazi, S.H. Wei, I. Parker, and M.D. Cahalan. 2004. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proceedings of the National Academy of Sciences U.S.A. 101: 998-1003. PMID: 14722354
Miller MJ, Safrina O, Parker I, Cahalan MD. 2004. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. Journal of Experimental Medicine 200: 847-56. PMID: 15466619
Okada, T., M.J. Miller, I. Parker, M.F. Krummel, M. Neighbors, S.B. Hartley, A. O’Garra, M.D. Cahalan, and J.G. Cyster. 2005. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS, Biology 3:1047-061. PMID: 15857154
Zinselmeyer, B.H., Dempster, J., Gurney, A.M., Wokosin, D., Miller, M.J., Ho, H., Millington, O.R., Smith, K.M., Rush, C.M., Parker, I., Cahalan, M.D., Brewer, J.M., Garside, P. 2005. In situ characterisation of CD4+ T cell behaviour in lymphoid tissues during the induction of oral priming and tolerance. Journal of Experimental Medicine 201: 1815-1823. PMID: 15928201
Wei, S.H., H. Rosen, M.P. Matheu, M.G. Sanna, S-K. Wang, E. Jo, C-H Wong, I. Parker, and M.D. Cahalan. 2005. S1P1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nature Immunology 6, 1228-1235. PMID: 16273098
Cahalan, M.D. and I. Parker. 2005. Close encounters of the first and second kind: T–DC and T–B interactions in the lymph node. Seminars in Immunology 17: 442–451. PMID: 16263308
Sanna, M.G., S.K. Wang, P.J. Gonzalez-Cabrera, A. Don, D. Marsolais, M.P. Matheu, S.H. Wei, I. Parker, E. Jo, W.C. Cheng, M.D. Cahalan, C.H. Wong, H. Rosen. 2006. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nature Chemical Biology 2:434-441. PMID: 16829954
Wei, S.H., O. Safrina, Y. Yu, K.R. Garrod, M.D. Cahalan, and I. Parker. 2007 Ca2+ signals in CD4+ T cells during early contacts with antigen-bearing dendritic cells in lymph node. Journal of Immunology 179: 1586-1594. PMID: 17609379
Garrod, K.R., S.H. Wei, I. Parker, and M.D. Cahalan. 2007. Natural killer cells actively patrol peripheral lymph nodes forming stable conjugates to eliminate MHC-mismatched targets. Proceedings of the National Academy of Sciences U.S.A. 104: 12081-12086. PMID: 17609379
Matheu, M.P., J.A. Deane, I. Parker, D.A. Fruman, and M.D. Cahalan. 2007 Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. Journal of Immunology 179: 2261-2269. PMID: 17675487
Cahalan, M.D. and I. Parker. 2008. Choreography of cell motility and interaction dynamics imaged by two-photon microscopy in lymphoid organs. Annual Review of Immunology 26: 585-626. PMID: 18173372
Sen, D., T.J. Deerinck, M.H. Ellisman, I. Parker, and M.D. Cahalan. 2008. Quantum dots for tracking dendritic cells and priming an immune response in vitro and in vivo. PLoS ONE 10.1371/journal.pone.0003290. PMID: 18820727
Garrod, K.R., F-C. Liu, L.E. Forrest, I. Parker, S-M. Kang, and M.D. Cahalan. 2010. Natural killer cell patrolling and elimination of donor-derived dendritic cells favors indirect alloreactivity. Journal of Immunology 184: 2329-2336. PMID: 20139277
Sen, D., L. Forrest, T.B. Kepler, I. Parker, M.D. Cahalan. 2010. Selective and site-specific mobilization of dermal dendritic cells and Langerhans cells by Th1- and Th2-polarizing adjuvants. Proceedings of the National Academy of Sciences U.S.A. 107: 8334-9. PMID: 20404167
Khorshidi, M.A., B. Vanherberghen, J.M. Kowalewski, K.R. Garrod, S. Lindstrom, H. Andersson-Svahn, H. Brismar, M.D. Cahalan, and B. Onfelt. 2011. Analysis of transient migration behavior of natural killer cells imaged in situ and in vitro. Integrative Biology 3: 770-778. (cover illustration) PMID: 21687858
Matheu, M.P., Y. Su, M.L. Greenberg, C.A. Blanc, I. Parker, D.W. Scott, and M.D. Cahalan. 2012. Toll-like receptor 4-activated B cells out-compete Toll-like receptor 9-activated B cells to establish peripheral immunological tolerance. 2012. Proceedings of the National Academy of Sciences U.S.A. 109:E1258-66. PMID: 22511718
Germain RN, Robey EA, Cahalan MD. 2012. A decade of imaging cellular motility and interaction dynamics in the immune system. Science 336: 1676-81. PMID 22745423
Matheu, M.P., J.R. Teijaro, K.B. Walsh, M.L. Greenberg, D. Marsolais, I. Parker, H. Rosen, M.B.A. Oldstone, and M.D. Cahalan. 2013. Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy. PLoS-ONE 10.1371/journal.pone.0058033. PMID: 23533579
Manolopoulou, I., M.P. Matheu, M.D. Cahalan, M. West, and T.B. Kepler. 2013. Bayesian spatio-dynamic modeling in cell motility studies: learning nonlinear taxic fields guiding the immune response. Journal of the American Statistical Association, 107: 855-865
Greenberg, M.L., J.G. Weinger, M.P. Matheu, K.S. Carbajal, I. Parker, W.B. Macklin, T.E. Lane, and M.D. Cahalan. 2014. Two-photon imaging of remyelination of spinal cord axons by engrafted neural precursor cells in a viral model of multiple sclerosis. Proceedings of the National Academy of Sciences U.S.A. 111(22):E2349-55. PMID: 24843159
Matheu, M.P., S. Othy, M.L. Greenberg, T.X. Dong, M. Schuijs, K. Deswarte, H. Hammad, B.N. Lambrecht, I. Parker, and M.D. Cahalan. 2015. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nature Communications 6:6219. doi: 10.1038/ncomms7219. PMID: 25653051
Dong TX, Othy S, Jairaman A, Skupsky J, Zavala A, Parker I, Dynes JL, Cahalan MD. 2017. T-cell calcium dynamics visualized in a ratiometric tdTomato-GCaMP6f transgenic reporter mouse. Elife 6. PMID: 29239725
McIntyre, L.L., S.A. Greilach, S. Othy, I. Sears-Kraxberger, B. Wi, J. Ayala-Angulo, E. Vu, Q. Pham, J. Silva, K. Dang, F. Rezk, O. Steward, M.D. Cahalan, T.E. Lane, and C.M. Walsh. 2020. Regulatory T cells promote remyelination in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis following human neural stem cell transplant. Neurobiology of Disease. 140:104868. PMID: 32276110
Othy S, Jairaman A, Dynes JL, Dong TX, Tune C, Yeromin AV, Zavala A, Akunwafo C, Chen F, Parker I, Cahalan MD. 2020. Regulatory T cells suppress Th17 cell Ca2+ signaling in the spinal cord during murine autoimmune neuroinflammation. Proceedings of the National Academy of Sciences U.S.A. 117: 20088-99. PMID: 32732436
NIH RO1 NS14609, "Molecular Mechanisms of Ion Channels in T Lymphocytes". 1978-present.
NIH RO1 GM41514, "Functional Imaging of Lymphocyte Motility and Cell Interactions in Lymph Node". 1984-2014.
NIH R21 AI117555 "A Transgenic Mouse Line to Map Cell-Type Specific Calcium Signals In Vivo." 2015-2017.
NIH RO1 AI121945. "Cellular and Molecular Mechanisms of Regulatory T Cells in EAE." 07/01/16-06/30/21
Biophysical Society 1973-present. Councilor 2008-2011
Society of General Physiologists member since 1978. Councilor 1993-1995, President 1998, Traveling Scholar Award 2011, Journal of General Physiology Editorial Board 1987-98, Advisory Editor 2002-present
Physiological Reviews Editorial Board 2002-2007
American Association of Immunologists
Cellular and Molecular Biosciences
Institute for Immunology, Cancer Center