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. 1996 Apr 1;183(4):1367–1375. doi: 10.1084/jem.183.4.1367

Visualization, characterization, and turnover of CD8+ memory T cells in virus-infected hosts

PMCID: PMC2192476  PMID: 8666895

Abstract

The cellular basis of T cell memory is a controversial issue and progress has been hampered by the inability to induce and to trace long- term memory T cells specific for a defined antigen in vivo. By using the murine model of lymphocytic choriomeningitis virus (LCMV) infection and an adoptive transfer system with CD8+ T cells from transgenic mice expressing an LCMV-specific T cell receptor, a population of authentic memory T cells specific for LCMV was generated and analyzed in vivo. The transgenic T cells that have expanded (1,000-fold) and then decreased (10-fold) in LCMV-infected C57BL/6 recipient mice exhibited the following characteristics: they were (a) of larger average cell size than their naive counterparts but smaller than day 8 effector cells; (b) heterogeneous with respect to expression of cell surface "memory" markers; and (c) directly cytolytic when isolated from recipient spleens. The time-dependent proliferative activity of these LCMV-specific memory T cells was analyzed in the recipients by bromodeoxyuridine labeling experiments in vivo. The experiments revealed that LCMV-specific CD8+ memory T cells can persist in LCMV- immune mice for extended periods of time (>2 mo) in the absence of cell division; the memory population as a whole survived beyond 11 mo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allouche M., Owen J. A., Doherty P. C. Limit-dilution analysis of weak influenza-immune T cell responses associated with H-2Kb and H-2Db. J Immunol. 1982 Aug;129(2):689–693. [PubMed] [Google Scholar]
  2. Baron J. L., Madri J. A., Ruddle N. H., Hashim G., Janeway C. A., Jr Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med. 1993 Jan 1;177(1):57–68. doi: 10.1084/jem.177.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Battegay M., Cooper S., Althage A., Bänziger J., Hengartner H., Zinkernagel R. M. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J Virol Methods. 1991 Jun;33(1-2):191–198. doi: 10.1016/0166-0934(91)90018-u. [DOI] [PubMed] [Google Scholar]
  4. Bell E. B., Sparshott S. M. Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 1990 Nov 8;348(6297):163–166. doi: 10.1038/348163a0. [DOI] [PubMed] [Google Scholar]
  5. Bradley L. M., Croft M., Swain S. L. T-cell memory: new perspectives. Immunol Today. 1993 May;14(5):197–199. doi: 10.1016/0167-5699(93)90161-D. [DOI] [PubMed] [Google Scholar]
  6. Bruno L., Kirberg J., von Boehmer H. On the cellular basis of immunological T cell memory. Immunity. 1995 Jan;2(1):37–43. doi: 10.1016/1074-7613(95)90077-2. [DOI] [PubMed] [Google Scholar]
  7. Budd R. C., Cerottini J. C., MacDonald H. R. Selectively increased production of interferon-gamma by subsets of Lyt-2+ and L3T4+ T cells identified by expression of Pgp-1. J Immunol. 1987 Jun 1;138(11):3583–3586. [PubMed] [Google Scholar]
  8. Byrne J. A., Butler J. L., Cooper M. D. Differential activation requirements for virgin and memory T cells. J Immunol. 1988 Nov 15;141(10):3249–3257. [PubMed] [Google Scholar]
  9. Celada F. The cellular basis of immunologic memory. Prog Allergy. 1971;15:223–267. [PubMed] [Google Scholar]
  10. Cerottini J. C., MacDonald H. R. The cellular basis of T-cell memory. Annu Rev Immunol. 1989;7:77–89. doi: 10.1146/annurev.iy.07.040189.000453. [DOI] [PubMed] [Google Scholar]
  11. Christensen J. P., Andersson E. C., Scheynius A., Marker O., Thomsen A. R. Alpha 4 integrin directs virus-activated CD8+ T cells to sites of infection. J Immunol. 1995 May 15;154(10):5293–5301. [PubMed] [Google Scholar]
  12. Constant S., Zain M., West J., Pasqualini T., Ranney P., Bottomly K. Are primed CD4+ T lymphocytes different from unprimed cells? Eur J Immunol. 1994 May;24(5):1073–1079. doi: 10.1002/eji.1830240510. [DOI] [PubMed] [Google Scholar]
  13. Croft M., Bradley L. M., Swain S. L. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol. 1994 Mar 15;152(6):2675–2685. [PubMed] [Google Scholar]
  14. Ehlers S., Smith K. A. Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med. 1991 Jan 1;173(1):25–36. doi: 10.1084/jem.173.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Farber D. L., Luqman M., Acuto O., Bottomly K. Control of memory CD4 T cell activation: MHC class II molecules on APCs and CD4 ligation inhibit memory but not naive CD4 T cells. Immunity. 1995 Mar;2(3):249–259. doi: 10.1016/1074-7613(95)90049-7. [DOI] [PubMed] [Google Scholar]
  16. Fuchs E. J., Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992 Nov 13;258(5085):1156–1159. doi: 10.1126/science.1439825. [DOI] [PubMed] [Google Scholar]
  17. Gray D., Matzinger P. T cell memory is short-lived in the absence of antigen. J Exp Med. 1991 Nov 1;174(5):969–974. doi: 10.1084/jem.174.5.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hou S., Hyland L., Ryan K. W., Portner A., Doherty P. C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature. 1994 Jun 23;369(6482):652–654. doi: 10.1038/369652a0. [DOI] [PubMed] [Google Scholar]
  19. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  20. Inaba K., Steinman R. M. Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release. J Exp Med. 1984 Dec 1;160(6):1717–1735. doi: 10.1084/jem.160.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kearney E. R., Pape K. A., Loh D. Y., Jenkins M. K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity. 1994 Jul;1(4):327–339. doi: 10.1016/1074-7613(94)90084-1. [DOI] [PubMed] [Google Scholar]
  22. Kyburz D., Aichele P., Speiser D. E., Hengartner H., Zinkernagel R. M., Pircher H. T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides. Eur J Immunol. 1993 Aug;23(8):1956–1962. doi: 10.1002/eji.1830230834. [DOI] [PubMed] [Google Scholar]
  23. Lau L. L., Jamieson B. D., Somasundaram T., Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994 Jun 23;369(6482):648–652. doi: 10.1038/369648a0. [DOI] [PubMed] [Google Scholar]
  24. Lee W. T., Yin X. M., Vitetta E. S. Functional and ontogenetic analysis of murine CD45Rhi and CD45Rlo CD4+ T cells. J Immunol. 1990 May 1;144(9):3288–3295. [PubMed] [Google Scholar]
  25. Luqman M., Bottomly K. Activation requirements for CD4+ T cells differing in CD45R expression. J Immunol. 1992 Oct 1;149(7):2300–2306. [PubMed] [Google Scholar]
  26. Mackay C. R. Immunological memory. Adv Immunol. 1993;53:217–265. doi: 10.1016/s0065-2776(08)60501-5. [DOI] [PubMed] [Google Scholar]
  27. McFarland H. I., Nahill S. R., Maciaszek J. W., Welsh R. M. CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992 Aug 15;149(4):1326–1333. [PubMed] [Google Scholar]
  28. McHeyzer-Williams M. G., Davis M. M. Antigen-specific development of primary and memory T cells in vivo. Science. 1995 Apr 7;268(5207):106–111. doi: 10.1126/science.7535476. [DOI] [PubMed] [Google Scholar]
  29. McKnight A. J., Perez V. L., Shea C. M., Gray G. S., Abbas A. K. Costimulator dependence of lymphokine secretion by naive and activated CD4+ T lymphocytes from TCR transgenic mice. J Immunol. 1994 Jun 1;152(11):5220–5225. [PubMed] [Google Scholar]
  30. Michie C. A., McLean A., Alcock C., Beverley P. C. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature. 1992 Nov 19;360(6401):264–265. doi: 10.1038/360264a0. [DOI] [PubMed] [Google Scholar]
  31. Moskophidis D., Assmann-Wischer U., Simon M. M., Lehmann-Grube F. The immune response of the mouse to lymphocytic choriomeningitis virus. V. High numbers of cytolytic T lymphocytes are generated in the spleen during acute infection. Eur J Immunol. 1987 Jul;17(7):937–942. doi: 10.1002/eji.1830170707. [DOI] [PubMed] [Google Scholar]
  32. Müllbacher A. The long-term maintenance of cytotoxic T cell memory does not require persistence of antigen. J Exp Med. 1994 Jan 1;179(1):317–321. doi: 10.1084/jem.179.1.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Oehen S., Waldner H., Kündig T. M., Hengartner H., Zinkernagel R. M. Antivirally protective cytotoxic T cell memory to lymphocytic choriomeningitis virus is governed by persisting antigen. J Exp Med. 1992 Nov 1;176(5):1273–1281. doi: 10.1084/jem.176.5.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Razvi E. S., Welsh R. M., McFarland H. I. In vivo state of antiviral CTL precursors. Characterization of a cycling cell population containing CTL precursors in immune mice. J Immunol. 1995 Jan 15;154(2):620–632. [PubMed] [Google Scholar]
  35. Salmon M., Kitas G. D., Bacon P. A. Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones. J Immunol. 1989 Aug 1;143(3):907–912. [PubMed] [Google Scholar]
  36. Sanders M. E., Makgoba M. W., June C. H., Young H. A., Shaw S. Enhanced responsiveness of human memory T cells to CD2 and CD3 receptor-mediated activation. Eur J Immunol. 1989 May;19(5):803–808. doi: 10.1002/eji.1830190504. [DOI] [PubMed] [Google Scholar]
  37. Sanders M. E., Makgoba M. W., Sharrow S. O., Stephany D., Springer T. A., Young H. A., Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
  38. Sanders M. E., Makgoba M. W., Shaw S. Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today. 1988 Jul-Aug;9(7-8):195–199. doi: 10.1016/0167-5699(88)91212-1. [DOI] [PubMed] [Google Scholar]
  39. Schittek B., Rajewsky K. Maintenance of B-cell memory by long-lived cells generated from proliferating precursors. Nature. 1990 Aug 23;346(6286):749–751. doi: 10.1038/346749a0. [DOI] [PubMed] [Google Scholar]
  40. Selin L. K., Nahill S. R., Welsh R. M. Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J Exp Med. 1994 Jun 1;179(6):1933–1943. doi: 10.1084/jem.179.6.1933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  42. Swain S. L. Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity. 1994 Oct;1(7):543–552. doi: 10.1016/1074-7613(94)90044-2. [DOI] [PubMed] [Google Scholar]
  43. Tough D. F., Sprent J. Turnover of naive- and memory-phenotype T cells. J Exp Med. 1994 Apr 1;179(4):1127–1135. doi: 10.1084/jem.179.4.1127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tripp R. A., Hou S., Doherty P. C. Temporal loss of the activated L-selectin-low phenotype for virus-specific CD8+ memory T cells. J Immunol. 1995 Jun 1;154(11):5870–5875. [PubMed] [Google Scholar]
  45. Van de Velde H., Lorré K., Bakkus M., Thielemans K., Ceuppens J. L., de Boer M. CD45RO+ memory T cells but not CD45RA+ naive T cells can be efficiently activated by remote co-stimulation with B7. Int Immunol. 1993 Nov;5(11):1483–1487. doi: 10.1093/intimm/5.11.1483. [DOI] [PubMed] [Google Scholar]
  46. Zinkernagel R. M., Leist T., Hengartner H., Althage A. Susceptibility to lymphocytic choriomeningitis virus isolates correlates directly with early and high cytotoxic T cell activity, as well as with footpad swelling reaction, and all three are regulated by H-2D. J Exp Med. 1985 Dec 1;162(6):2125–2141. doi: 10.1084/jem.162.6.2125. [DOI] [PMC free article] [PubMed] [Google Scholar]

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