Louis J. Picker, M.D.

Some T cells are the immune system's memory chips. Before the immune system can mount an effective attack on a disease-causing microorganism, they must form a subset of "memory" T cells specific for that organism. These "memory" T cells orchestrate immune elimination of the invader and remain in the blood and tissues so that the system can mount another counterattack should the foreign agent invade again. Memory T cell activity is also the key to explaining how vaccines work. Vaccines expose the immune system to weakened or noninfectious forms of pathogens, thus activating T cell memory and tricking the system into generating these critical disease-fighting cells.

Researchers in Louis Picker's laboratory focus their studies on memory T cell biology in human and nonhuman primates. They investigate the physiology of T cell memory and effector responses, including mechanisms that control "selection" of the memory repertoire, the functional specialization of the memory population, and the elements involved in T cell homeostasis and regeneration.

At the same time, these scientists are seeking to determine the basis of effective immunity to certain chronic human pathogens, particularly HIV/SIV and cytomegalovirus, and are working on prophylactic and/or therapeutic vaccines against these pathogens. Finally, they are studying how memory T cells are reconstituted after HIV-1 infection or bone marrow transplantation.

Picker and his colleagues have developed special expertise in the quantification and functional characterization of antigen-specific memory T cells. They exploit these technologies in the examination of human subjects and rhesus macaque models of chronic viral infection.


Biography

Louis Picker graduated from UCLA with a B.S. in bacteriology in 1978 and took his M.D. degree at the University of California at San Francisco in 1982. After residency training in pathology at Beth Israel Hospital, Boston, and postdoctoral training in immunology at Stanford University Medical Center, he was appointed assistant professor and then associate professor of pathology at the University of Texas Southwestern Medical Center at Dallas. In 1999 he came to OHSU and ONPRC as professor of pathology/molecular microbiology and immunology in the OHSU School of Medicine and head of the Division of Pathobiology and Immunology.

Publications

  1. Picker L.J., Kishimoto T.K., Smith C.W., Warnke R.A., and Butcher E.C.  ELAM-1 is an adhesion molecule for skin-homing lymphocytes.  Nature 349:796-799, 1991.
  2. Picker L.J., Warnock R.A., Burns A.R., Doerschuk C.M., Berg E.L., Butcher E.C. The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140.  Cell 66:921-933, 1991.
  3. Picker L.J., Treer J.R., Ferguson-Darnell B., Collins P., Buck D., and Terstappen L.W.M.M.  Control of lymphocyte homing in man: I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory transition.  J. Immunol. 150:1105-1121, 1993.
  4. Picker LJ, Treer JR, Ferguson-Darnell B, Collins P, Bergstresser P, and Terstappen LWMM.  Control of lymphocyte homing in man: II. Differential regulation of the T cell skin-selective homing receptor CLA.  J. Immunol. 150:1122-1136. 1993.
  5. Picker L.J., Singh M.K., Zdraveski Z., Treer J.R., Waldrop S.L., Bergstresser P.R., and Maino V.C.  Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry, Blood., 86:1408-1419, 1995.
  6. Butcher E., Picker L.J.  Lymphocyte homing and homeostasis, Science, 272:60-66, 1996.
  7. Waldrop S.L., Picher C.J., Peterson D., Maino V.C. and Picker L.J. Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: Evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency, J. Clin. Invest., 99:1739-1750, 1997.
  8. Waldrop S.L., Davis, K.A., Maino V.C., and Picker L.J.  Normal human CD4+ memory T cells display broad heterogeneity in their activation threshold for cytokine synthesis,  J. Immunol., 161:5284, 1998.
  9. Pitcher C.J., Quittner C., Peterson D.M., Connors M., Koup R.A., Maino V.C., and Picker L.J.  HIV-1 specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression, Nature Medicine, 5:518-525, 1999.
  10. McFarland RD., Douek DC., Koup RA, and Picker LJ.  Identification of a human recent thymic emigrant phenotype, Proc. Natl. Acad. Sci., USA, 97:4215-4220, 2000.
  11. Betts MR, Casazza JP, Patterson BA, Waldrop S, Trigona W, Fu T-M, Kern F, Picker LJ, and Koup RA.  Immunodominant HIV-specific CD8+ T cell responses cannot be predicted by MHC class I haplotype, J. Virol., 74:9144-9151, 2000.
  12. Bitmansour AD, Waldrop SL, Pitcher CJ, Khatamzas E, Kern F, Maino VC, and Picker LJ.  Clonotypic structure of the human CD4+ memory T cell response to CMV, J. Immunol., 167:1151-1163, 2001.
  13. Casazza JP., Betts MR,  Picker  LJ,  and Koup RA.  Decay kinetics of HIV-specific CD8+ T-cells in peripheral blood after initiation of highly active anti-retroviral therapy, J. Virol. 75:6508-6516, 2001.
  14. Maecker HT, Dunn HS, Suni MA, Khatamzas E, Pitcher CJ, Bunde T, Persaud N, Trigona W., Fu T-M, Sinclair E, Bredt BM, McCune JM, Maino VC, Kern F, and Picker LJ. Use of overlapping peptide mixtures as antigens for cytokine flow cytometry, J. Immunol. Methods, 255:27-40, 2001.
  15. Suni MA, Ghanekar SA, Houck DW, Maeker HT, Wormsley SB, Picker LJ, Moss RB, and Maino VC. CD4+/CD8dim T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens,. Eur. J. Immunol., 31:2512-2520, 2001.
  16. Betts MR, Ambrozak DA, Douek DC, Bonhoeffer SE, Brenchley JM, Casazza JP, Koup RA, and Picker LJ. Analysis of total HIV-specific CD4+ and CD8+ T cell responses: Relationship to viral load in untreated HIV-1 infection, J. Virol., 75:11983-11991, 2001.
  17. Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, and Picker LJ.  Development and homeostasis of T cell memory in rhesus macaque, J. Immunol., 168:29-43, 2002.
  18. Bitmansour AD, Douek, DC, Maino VC, Picker LJ.  Direct ex vivo analysis of human CD4+ memory T cell activation requirements at the single clonotype level, J. Immunol., 169:1207-1218, 2002.
  19. Douek, D.C., Picker, L.J., and Koup, R.A. T cell dynamics in HIV-1 infection. Annu. Rev. Immunol. 21:265-304, 2003.
  20. Walker JM, Maecker HT, Maino VC, and Picker LJ. Multi-color flow cytometric analysis in SIV-Infected rhesus macaques. Cytometry, 4th edition, in “Methods in Cell Biology” Series (vol. 75), Z. Darzynkiewicz, M. Roederer, H. Tanke, eds., Academic Press/Elsevier, San Diego, p.535-557, 2004.
  21. Picker LJ, Hagen SI, Lum R, Reed-Inderbitzin EF, Daly, LM, Sylwester, AW, Walker JM, Siess DC, Piatak, Jr., M, Wang C, Allison DB, Maino VC, Lifson JD, Kodama T, Axthelm MK. Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive SIV infection, J. Exp. Med., 200:1299-1314, 2004.
  22. Picker LJ, Watkins DI. HIV pathogenesis: the first cut is the deepest. Nat. Immunol., 6:430-432, 2005.
  23. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, Sleath PR, Grabstein KH, Hosken NA, Kern F, Nelson JA, and Picker LJ.  Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med., 202:673-685, 2005.
  24. Grossman Z, Meier-Schellersheim M, Paul WE, and Picker LJ. Pathogenesis of HIV infection: What the virus spares is as important as what it destroys. Nat. Med. 12:289-295, 2006.
  25. Picker LJ, Reed-Inderbitzin, EF, Hagen SI, Edgar JB, Hansen, SG, Legasse, A, Planer S, Piatak, Jr., M, Lifson, JD, Maino VC, Axthelm MK, and Villinger F. IL-15 induces CD4+ effector memory T cell production and tissue emigration in non-human primates. J. Clin. Invest., 116:1514-1524, 2006.
  26. Picker LJ. Immunopathogenesis of acute AIDS virus infection. Curr. Opin. Immunol., 18:399-405, 2006.
  27.    Messaoudi I, Warner J, Fischer M, Park B, Hill B, Mattison J, Lane MA, Roth GS, Ingram DK, Picker LJ, Douek DC, Mori M and Nikolich-Zugich J.  Delay of T-cell senescence by caloric restriction in aged long-lived non-human primates. Proc. Natl. Acad. Sci.,USA, 103:19448-53, 2006.
  28.    Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriquez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG and Douek DC. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med., 12:1365-71, 2006.
  29. Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar J, Planer SL, Legasse A, Sylwester AW, Piatak, Jr., M, Lifson, JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, and Picker LJ. Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection, J. Exp. Med., 204:2171-2185, 2007.
  30. Price DA, Bitmansour AD, Walker JM, Edgar JB, Axthelm MK, Douek DC, and Picker LJ. Induction and evolution of cytomegalovirus-specific CD4+ T cell clonotypes in rhesus macaques. J. Immunol., 180:269-280, 2008.
  31. Grossman Z, and Picker LJ.  Pathogenic mechanisms in SIV infection.  Curr. Opin. HIV AIDS, 3:380-386, 2008.
  32. Hansen SG, Vieville C, Whizin N, Coyne-Johnson L, Siess DC, Drummond DD, Legasse AW, Axthelm  MK, Oswald K, Trubey CM, Piatak, Jr. M, Lifson JD, Nelson JA, Jarvis  MA, and Picker LJ.  Effector-memory T cell responses are associated with protection of rhesus monkeys from mucosal SIV challenge. Nat. Med., 15(3):293-299, 2009.
  33. Okoye A, Park H, Rohankhedkar M, Coyne-Johnson L, Lum R, Walker JM, Planer SL, Legasse AW, Sylwester AW, Piatak, Jr. M, Lifson JD, Sodora DL, Axthelm MK, Schmitz JE, and Picker LJ. Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis, J. Exp. Med., 206:1575-1588, 2009.
  34. Hansen SG, Powers C, Richards R, Ventura AB, Ford JC, Siess D, Axthelm MK, Nelson JA, Jarvis Ma, Picker LJ*, and Früh K*. Evasion of CD8+ T cells is critical for super-infection by cytomegalovirus. Science, 328:102-106, 2010. (*co-corresponding authors).
  35. Corey L., Autran B., Picker L., and the Global HIV Vaccine Enterprise Working Group. Bridging the gaps between fundamental, preclinical and clinical research: Report from a global HIV Vaccine Enterprise working group.  Nature Precedings, doi:10.1038/npre.2010.4799.2 (posted 7 Sep 2010).
  36. Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, Whizin N, Oswald K, Shoemaker R, Swanson, T, Legasse AW, Axthelm MK, Nelson JA, Jarvis MA, Parks CL, Chiuchiolo MJ, Piatak, Jr. M, Lifson JD, and Picker, LJ. Profound early control of highly pathogenic SIV by an effector-memory T cell vaccine, Nature, in press.
  37. Corey L., Nabel GJ, Dieffenbach C, Gilbert P, Haynes BF, Johnston M, Kublin J, Lane HC, Pantaleo G, Picker LJ, and Fauci AS. HIV-1 vaccines and adaptive trial designs. Science Translation Med., Vol 3, Issue 79, 79ps13, 2011

 

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