Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Jun 1;179(6):1933–1943. doi: 10.1084/jem.179.6.1933

Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses

PMCID: PMC2191532  PMID: 8195718

Abstract

Analyses of the relationships between different viruses and viral proteins have focused on homologies between linear amino acid sequences, but cross-reactivities at the level of T cell recognition may not be dependent on a conserved linear sequence of several amino acids. The CTL response to Pichinde virus (PV) and vaccinia virus (VV) in C57BL/6 mice previously immunized with lymphocytic choriomeningitis virus (LCMV) included the reactivation of memory cytotoxic T lymphocyte (CTL) specific to LCMV. Limiting dilution assays (LDA) demonstrated that at least part of this reactivation of memory cells in LCMV-immune mice related to cross-reactivity at the clonal level, even though acute infections with these viruses in nonimmune mice elicited CTL responses that did not cross-react in conventional bulk CTL assays. Precursor CTL (pCTL) to LCMV were generated in splenic leukocytes from LCMV-immune mice acutely infected with PV or VV when stimulated in vitro with only the second virus but not with uninfected peritoneal exudate cells (PECs). Cytotoxicity mediated by LCMV-specific CTL clones activated by PV infection was greatly inhibited by anti-CD8 antibody, suggesting that these memory CTL clones recognizing LCMV-infected targets were of low affinity. LCMV-immune splenocytes stimulated in vitro with PV or VV demonstrated a low but significant precursor frequency (p/f) to the heterologous viruses, and splenocytes from PV- or VV-immune mice when stimulated in vitro against LCMV generated a low but significant p/f to LCMV. Short-term CTL clones cross-reactive between LCMV and PV were derived from splenic leukocytes from LCMV-immune mice acutely infected with PV. To distinguish whether the cross-reactivity was directed against a viral peptide or a virus-induced endogenous cellular neoantigen, we demonstrated that a pCTL frequency to PV about 1/4-1/7 that of the frequency to LCMV could be generated from LCMV-immune splenic leukocytes stimulated with the immunodominant LCMV NP peptide. A partially homologous PV peptide generated from the equivalent site to the LCMV NP peptide did not sensitize targets to lysis by either LCMV- or PV-specific CTLs, suggesting that the cross-reactivity in killing was not due to evolutionarily conserved equivalent sequences. Experiments also indicated that prior immunity to one virus could modulate future primary immune responses to a second virus. Elevated pCTL frequencies to PV were seen after acute PV infection of LCMV- immune mice, and elevated pCTL frequencies to LCMV were seen after acute LCMV infection of PV- and VV-immune mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Full Text

The Full Text of this article is available as a PDF (1,010.4 KB).

Selected References

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

  1. Akbar A. N., Salmon M., Janossy G. The synergy between naive and memory T cells during activation. Immunol Today. 1991 Jun;12(6):184–188. doi: 10.1016/0167-5699(91)90050-4. [DOI] [PubMed] [Google Scholar]
  2. Anderson R. W., Bennink J. R., Yewdell J. W., Maloy W. L., Coligan J. E. Influenza basic polymerase 2 peptides are recognized by influenza nucleoprotein-specific cytotoxic T lymphocytes. Mol Immunol. 1992 Sep;29(9):1089–1096. doi: 10.1016/0161-5890(92)90041-u. [DOI] [PubMed] [Google Scholar]
  3. Bierer B. E., Burakoff S. J. T cell adhesion molecules. FASEB J. 1988 Jul;2(10):2584–2590. doi: 10.1096/fasebj.2.10.2838364. [DOI] [PubMed] [Google Scholar]
  4. Biron C. A., Natuk R. J., Welsh R. M. Generation of large granular T lymphocytes in vivo during viral infection. J Immunol. 1986 Mar 15;136(6):2280–2286. [PubMed] [Google Scholar]
  5. Bonomo A., Matzinger P. Thymus epithelium induces tissue-specific tolerance. J Exp Med. 1993 Apr 1;177(4):1153–1164. doi: 10.1084/jem.177.4.1153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carding S. R., Allan W., McMickle A., Doherty P. C. Activation of cytokine genes in T cells during primary and secondary murine influenza pneumonia. J Exp Med. 1993 Feb 1;177(2):475–482. doi: 10.1084/jem.177.2.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Demkowicz W. E., Jr, Ennis F. A. Vaccinia virus-specific CD8+ cytotoxic T lymphocytes in humans. J Virol. 1993 Mar;67(3):1538–1544. doi: 10.1128/jvi.67.3.1538-1544.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  9. Jennings S. R. Cross-reactive recognition of mouse cells expressing the bm3 and bm11 mutations within H-2Kb by H-2Kb-restricted herpes simplex virus-specific cytotoxic T lymphocytes. J Immunol. 1985 Nov;135(5):3530–3536. [PubMed] [Google Scholar]
  10. Kos F. J., Müllbacher A. IL-2-independent activity of IL-7 in the generation of secondary antigen-specific cytotoxic T cell responses in vitro. J Immunol. 1993 Jan 15;150(2):387–393. [PubMed] [Google Scholar]
  11. Kos F. J., Müllbacher A. Induction of primary anti-viral cytotoxic T cells by in vitro stimulation with short synthetic peptide and interleukin-7. Eur J Immunol. 1992 Dec;22(12):3183–3185. doi: 10.1002/eji.1830221224. [DOI] [PubMed] [Google Scholar]
  12. Krensky A. M., Sanchez-Madrid F., Robbins E., Nagy J. A., Springer T. A., Burakoff S. J. The functional significance, distribution, and structure of LFA-1, LFA-2, and LFA-3: cell surface antigens associated with CTL-target interactions. J Immunol. 1983 Aug;131(2):611–616. [PubMed] [Google Scholar]
  13. Kulkarni A. B., Morse H. C., 3rd, Bennink J. R., Yewdell J. W., Murphy B. R. Immunization of mice with vaccinia virus-M2 recombinant induces epitope-specific and cross-reactive Kd-restricted CD8+ cytotoxic T cells. J Virol. 1993 Jul;67(7):4086–4092. doi: 10.1128/jvi.67.7.4086-4092.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kuwano K., Reyes V. E., Humphreys R. E., Ennis F. A. Recognition of disparate HA and NS1 peptides by an H-2Kd-restricted, influenza specific CTL clone. Mol Immunol. 1991 Jan-Feb;28(1-2):1–7. doi: 10.1016/0161-5890(91)90080-4. [DOI] [PubMed] [Google Scholar]
  15. McCarthy S. A., Kaldjian E., Singer A. Characterization of anti-CD8-resistant cytolytic T lymphocytes induced by multivalent cross-linking of CD8 on precursor cells. J Immunol. 1989 Oct 1;143(7):2112–2119. [PubMed] [Google Scholar]
  16. 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]
  17. McIntyre K. W., Bukowski J. F., Welsh R. M. Exquisite specificity of adoptive immunization in arenavirus-infected mice. Antiviral Res. 1985 Oct;5(5):299–305. doi: 10.1016/0166-3542(85)90044-0. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Nahill S. R., Welsh R. M. High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response. J Exp Med. 1993 Feb 1;177(2):317–327. doi: 10.1084/jem.177.2.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ozols D. Y., Harnish D. G., Rawls W. E., Rosenthal K. L. Assessment of the specificity of cytotoxic T lymphocytes for the nucleoprotein of Pichinde virus using recombinant vaccinia viruses. Arch Virol. 1990;115(3-4):209–225. doi: 10.1007/BF01310531. [DOI] [PubMed] [Google Scholar]
  21. Rabin H., Hopkins R. F., 3rd, Ruscetti F. W., Neubauer R. H., Brown R. L., Kawakami T. G. Spontaneous release of a factor with properties of T cell growth factor from a continuous line of primate tumor T cells. J Immunol. 1981 Nov;127(5):1852–1856. [PubMed] [Google Scholar]
  22. Shimojo N., Maloy W. L., Anderson R. W., Biddison W. E., Coligan J. E. Specificity of peptide binding by the HLA-A2.1 molecule. J Immunol. 1989 Nov 1;143(9):2939–2947. [PubMed] [Google Scholar]
  23. Stitz L., Baenziger J., Pircher H., Hengartner H., Zinkernagel R. M. Effect of rabbit anti-asialo GM1 treatment in vivo or with anti-asialo GM1 plus complement in vitro on cytotoxic T cell activities. J Immunol. 1986 Jun 15;136(12):4674–4680. [PubMed] [Google Scholar]
  24. Strang G., Rickinson A. B. Multiple HLA class I-dependent cytotoxicities constitute the "non-HLA-restricted" response in infectious mononucleosis. Eur J Immunol. 1987 Jul;17(7):1007–1013. doi: 10.1002/eji.1830170717. [DOI] [PubMed] [Google Scholar]
  25. Stukart M. J., Boes J., Melief C. J. Recognition of H-2Kb mutant target cells by Moloney virus-specific cytotoxic T lymphocytes from bm13 (H-2Db-mutant) mice. II. Relationship of Kbm3 and Kbm11 in restriction specificities and allodeterminants. J Immunol. 1984 Jul;133(1):28–32. [PubMed] [Google Scholar]
  26. Tabi Z., Lynch F., Ceredig R., Allan J. E., Doherty P. C. Virus-specific memory T cells are Pgp-1+ and can be selectively activated with phorbol ester and calcium ionophore. Cell Immunol. 1988 May;113(2):268–277. doi: 10.1016/0008-8749(88)90026-3. [DOI] [PubMed] [Google Scholar]
  27. Tanaka Y., Tevethia S. S. In vitro selection of SV40 T antigen epitope loss variants by site-specific cytotoxic T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4348–4354. [PubMed] [Google Scholar]
  28. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  29. Tomkinson B. E., Maziarz R., Sullivan J. L. Characterization of the T cell-mediated cellular cytotoxicity during acute infectious mononucleosis. J Immunol. 1989 Jul 15;143(2):660–670. [PubMed] [Google Scholar]
  30. Weber E. L., Buchmeier M. J. Fine mapping of a peptide sequence containing an antigenic site conserved among arenaviruses. Virology. 1988 May;164(1):30–38. doi: 10.1016/0042-6822(88)90616-2. [DOI] [PubMed] [Google Scholar]
  31. Welsh R. M., Jr Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction. J Exp Med. 1978 Jul 1;148(1):163–181. doi: 10.1084/jem.148.1.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yang H. Y., Dundon P. L., Nahill S. R., Welsh R. M. Virus-induced polyclonal cytotoxic T lymphocyte stimulation. J Immunol. 1989 Mar 1;142(5):1710–1718. [PubMed] [Google Scholar]
  33. Yang H. Y., Joris I., Majno G., Welsh R. M. Necrosis of adipose tissue induced by sequential infections with unrelated viruses. Am J Pathol. 1985 Aug;120(2):173–177. [PMC free article] [PubMed] [Google Scholar]
  34. Yang H., Welsh R. M. Induction of alloreactive cytotoxic T cells by acute virus infection of mice. J Immunol. 1986 Feb 15;136(4):1186–1193. [PubMed] [Google Scholar]
  35. Yang H., Yogeeswaran G., Bukowski J. F., Welsh R. M. Expression of asialo GM1 and other antigens and glycolipids on natural killer cells and spleen leukocytes in virus-infected mice. Nat Immun Cell Growth Regul. 1985;4(1):21–39. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES