Advertisement

Acquisition of Mature Functional Responsiveness in T Cells: Programming for Function via Signaling

  • Ellen V. Rothenberg
  • Dan Chen
  • Rochelle A. Diamond
  • Mariam Dohadwala
  • Thomas J. Novak
  • Patricia M. White
  • Julia A. Yang-Snyder
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 292)

Abstract

Over fifteen years ago it was recognized that peripheral T lymphocytes are heterogeneous in their abilities to carry out particular functions. Distinct functional activities are associated with distinct cell-surface phenotypes.1 Thus, CD4+ cells are greatly enriched for the ability to provide growth and differentiation factors for other T and B cells, whereas CD8+ cells are correspondingly enriched for the ability to kill foreign or pathologically altered target cells. At the molecular level, we now understand that each of these functions reflects the transcriptional activation of particular sets of “response” genes, i.e., those encoding lymphokines and/or cytolytic molecules, when triggered by recognition of a foreign antigen. Thus, different T-cell subsets are defined by the fact that they respond to antigen by induction of different sets of genes. As all of these subsets are derived from common precursors, developing T cells must not only mature but also diverge in their properties in a regulated way. In this paper, we will consider how different programs of transcriptional inducibility become allocated to different sets of cells.

Keywords

Immature Thymocyte Killer Function Functional Lineage Major Histocompatibility Complex Ligand Cytolytic Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    J. Sprent and S. R. Webb, Function and specificity of T-cell subsets in the mouse, Adv. Immunol. 41:39 (1987).PubMedCrossRefGoogle Scholar
  2. 2.
    R. Ceredig, A. L. Glasebrook, and H. R. MacDonald, Phenotypic and functional properties of murine thymocytes. I. Precursors of CTLs and interleukin-2 producing cells are all contained within a subpopulation of “mature” thymocytes as analyzed by monoclonal antibodies and flow microfluorometry, J. Exp. Med. 155:358 (1982).PubMedCrossRefGoogle Scholar
  3. 3.
    R. Ceredig, D. P. Dialynas, F. W. Fitch, and H. R. MacDonald, Precursors of T-cell growth factor producing cells in the thymus: Ontogeny, frequency, and quantitative recovery in a subpopulation of phenotypically mature thymocytes defined by monoclonal antibody GK-1.5, J. Exp. Med. 158:1654 (1983).PubMedCrossRefGoogle Scholar
  4. 4.
    H. S. Teh, P. Kisielow, B. Scott, H. Kishi, Y. Uematsu, H. Bluthmann, and H. von Boehmer, Thymic major histocompatibility complex antigens and the α β; T-cell receptor determine the CD4/CD8 phenotype of T cells, Nature 335:229 (1988).PubMedCrossRefGoogle Scholar
  5. 5.
    W. C. Sha, C. A. Nelson, R. D. Newberry, D. M. Kranz, J. H. Russell, and D. Y. Loh, Positive and negative selection of an antigen receptor on T cells in transgenic mice, Nature 336:73 (1988).PubMedCrossRefGoogle Scholar
  6. 6.
    B. Scott, H. Bluthmann, H. S. Teh, and H. von Boehmer, The generation of mature T cells requires interaction of the α βT-cell receptor with major histocompatibility antigens, Nature 338:591 (1989).PubMedCrossRefGoogle Scholar
  7. 7.
    L. J. Berg, A. M. Pullen, B. Fazekas de St. Groth, D. Mathis, C. Benoist, and M. M. Davis, Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand, Cell 58:1035 (1989).]PubMedCrossRefGoogle Scholar
  8. 8.
    H. von Boehmer, H. S. Teh, and P. Kisielow, The thymus selects the useful, neglects the useless and destroys the harmful, Immunol. Today 10:57 (1989).CrossRefGoogle Scholar
  9. 9.
    E. V. Rothenberg, Death and transfiguration of cortical thymocytes: A reconsideration, Immunol. Today 11:116 (1990).PubMedCrossRefGoogle Scholar
  10. 10.
    J. P. Lugo, S. N. Krishnan, R. D. Sailor, and E. V. Rothenberg, Early precursor thymocytes can produce interleukin 2 upon stimulation with calcium ionophore and phorbol ester, Proc. Natl. Acad. Sci. USA 83:1862 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Palacios and H. von Boehmer, Requirements for growth of immature thymocytes from fetal and adult mice in vitro, Eur. J. Immunol. 16:12 (1986).PubMedCrossRefGoogle Scholar
  12. 12.
    R. C. Howe, J. W. Lowenthal, and H. R. MacDonald, Role of interleukin 1 in early T-cell development: Lyt-2-L3T4-thymocytes bind and respond in vitro to recombinant IL-1, J. Immunol. 137:3195 (1986).PubMedGoogle Scholar
  13. 13.
    K. L. McGuire and E. V. Rothenberg, Inducibility of interleukin-2 RNA expression in individual mature and immature T lymphocytes, EMBO J. 7:939 (1987).Google Scholar
  14. 14.
    R. C. Howe and H. R. MacDonald, Heterogeneity of immature (Lyt-2-/L3T4-) thymocytes. Identification of four major phenotypically distinct subsets differing in cell cycle status and in vitro activation requirements, J. Immunol. 140:1047 (1988).PubMedGoogle Scholar
  15. 15.
    E. V. Rothenberg, R. A. Diamond, K. A. Pepper, and J. A. Yang, IL-2 gene inducibility in T cells before T-cell receptor expression. Changes in signaling pathways and gene expression requirements during intrathymic maturation. J. Immunol. 144: 1614 (1990).PubMedGoogle Scholar
  16. 16.
    E. V. Rothenberg, R. A. Diamond, T. J. Novak, K. A. Pepper, and J. A. Yang, Mechanisms of effector lineage commitment in T-lymphocyte development, Devel. Biol., UCLA Symp. in Molec. & Cell Biol. 125:225 (1990).Google Scholar
  17. 17.
    B. Caplan and E. V. Rothenberg, High-level secretion of IL-2 by a subset of proliferating thymic lymphoblasts, J. Immunol. 133: 1983 (1984).PubMedGoogle Scholar
  18. 18.
    K. Heeg, C. Steeg, J. Schmitt, and H. Wagner, Frequency analysis of class I MHC-reactive Lyt2+ and class II MHC-reactive L3T4+ IL2-secreting lymphocytes, J. Immunol. 138:4121 (1987).PubMedGoogle Scholar
  19. 19.
    D. E. Kehn, L. B. Lachmann, and P. D. Greenberg, Lyt-2+ cells. Requirements for concanavalin A-induced proliferation and interleukin 2 production, J. Immunol. 139:2880 (1987).Google Scholar
  20. 20.
    T. Mizuochi, D. J. McLean, and A. Singer, IL-2 as a co-factor for lymphokine-secreting CD8+ murine T cells, J. Immunol. 141:1571 (1988).PubMedGoogle Scholar
  21. 21.
    Y. Samstag, F. Emmrich, and T. Staehelin, Activation of human T lymphocytes: Differential effects of CD3-and CD8-mediated signals, Proc. Natl. Acad. Sci. USA 85:9689 (1988).PubMedCrossRefGoogle Scholar
  22. 22.
    D. L. Mueller, M. K. Jenkins, and R. H. Schwartz, Clonal expansion versus functional clonal activation: A costimulatory signaling pathway determines the outcome of T-cell antigen receptor occupancy, Ann. Rev. Immunol. 7:445 (1989).CrossRefGoogle Scholar
  23. 23.
    H. Wagner, K. Heeg, and C. Hardt, Multiple signals required in cytolytic T-cell responses, Prog. Immunol. VI:386 (1986).Google Scholar
  24. 24.
    J. A. Garcia-Sanz, G. Plaetinck, F. Velotti, D. Masson, J. Tschopp, and H. R. MacDonald, Perforin is present only in normal activated Lyt2+ T lymphocytes and not in L3T4+ cells, but the serine protease granzyme A is made by both subsets, EMBO J. 6:933 (1987).PubMedGoogle Scholar
  25. 25.
    J. D. Pfeifer, D. T. McKenzie, S. L. Swain, and R. W. Dutton, B-cell stimulatory factor 1 (interleukin 4) is sufficient for the proliferation and differentiation of lectin-stimulated cytolytic T-lymphocyte precursors, J. Exp. Med. 166:1464 (1987).PubMedCrossRefGoogle Scholar
  26. 26.
    J. W. L. Hooton, C. L. Miller, C. D. Helgason, R. C. Bleackley, S. Gillis, and V. Paetkau, Development of precytotoxic T cells in cyclosporine-suppressed mixed lymphocyte reactions, J. Immunol. 144:816 (1990).PubMedGoogle Scholar
  27. 27.
    H. von Boehmer, P. Kisielow, W. Leiserson, and W. Haas, Lyt-2-T-cell independent functions of Lyt-2+ cells stimulated with antigen or Con A, J. Immunol. 133:59 (1984).Google Scholar
  28. 28.
    G. D. Powers, A. K. Abbas, and R. A. Miller, Frequencies of IL-2 and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations, J. Immunol. 140:3352 (1988).PubMedGoogle Scholar
  29. 29.
    K. Hayakawa and R. R. Hardy, Murine CD4+ T-cell subsets defined, J. Exp. Med. 168:1825 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    K. Hayakawa and R. R. Hardy, Phenotypic and functional alteration of CD4+ T cells after antigen stimulation. Resolution of two populations of memory T cells that both secrete interleukin 4, J. Exp. Med. 169:2245 (1989).PubMedCrossRefGoogle Scholar
  31. 31.
    E. H. Davidson, How embryos work: A comparative view of diverse modes of cell fate specification, Development 108:365 (1990).PubMedGoogle Scholar
  32. 32.
    A. Weiss and J. D. Stobo, Requirement for the coexpression of T3 and the T-cell antigen receptor on a malignant human T-cell line, J. Exp. Med. 160:1284 (1984).PubMedCrossRefGoogle Scholar
  33. 33.
    A. Truneh, F. Albert, P. Golstein and A. M. Schmitt-Verhulst, Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester, Nature 313:318 (1985).PubMedCrossRefGoogle Scholar
  34. 34.
    J. J. Farrar, J. Fuller-Farrar, P. L. Simon, M. L. Hilfiker, B. M. Stadler, and W. L. Farrar, Thymoma production of T-cell growth factor (interleukin 2), J. Immunol. 125:2555 (1980).PubMedGoogle Scholar
  35. 35.
    G. R. Crabtree, Contingent genetic regulatory events in T-lymphocyte activation, Science 243:355 (1989).PubMedCrossRefGoogle Scholar
  36. 36.
    B. Hoyos, D. W. Ballard, E. Böhnlein, M. Siekevitz, and W. C. Greene, Kappa B-specific DNA binding proteins: Role in the regulation of human interleukin-2 gene expression, Science 244:457 (1989).PubMedCrossRefGoogle Scholar
  37. 37.
    K. Muegge, T. M. Williams, J. Kant, M. Karin, R. Chiu, A. Schmidt, U. Siebenlist, H. A. Young, and S. K. Durum, Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1, Science 246:249 (1989).PubMedCrossRefGoogle Scholar
  38. 38.
    E. Serfling, R. Barthelmas, I. Pfeuffer, B. Schenk, S. Zarius, R. Swoboda, F. Mercurio, and M. Karin, Ubiquitous and lymphocyte-specific factors are involved in the induction of the mouse interleukin-2 gene in T lymphocytes, EMBO J. 8:465 (1989).PubMedGoogle Scholar
  39. 39.
    T. J. Novak, D. Chen, and E. V. Rothenberg, Interleukin 1 synergy with phosphoinositide pathway agonists for induction of interleukin 2 gene expression: molecular basis of costimulation. (1990, submitted for publication).Google Scholar
  40. 40.
    F. Shirakawa, M. Chedid, J. Suttles, B. A. Pollok, and S. B. Mizel, Interleukin-1 and cyclic AMP induce. immunoglobulin light-chain expression via activation of an NF-/cB-like DNA-binding protein, Mol. Cell. Biol. 9:959 (1989).PubMedGoogle Scholar
  41. 41.
    K. L. McGuire, J. A. Yang, and E. V. Rothenberg, Influence of activating stimulus on functional phenotype: Interleukin-2 mRNA accumulation differentially induced by ionophore and receptor ligands in subsets of murine T cells, Proc. Natl. Acad. Sci. USA 85:6503 (1988).PubMedCrossRefGoogle Scholar
  42. 42.
    X. Paliard, R. de Waal Malefijt, H. Yssel, D. Blanchard, L. Chretien, J. Abrams,and J. de Vries, Simultaneous production of IL-2, IL-4, and IFN-&by activated human CD4+ and CD8+ T-cell clones, J. Immunol. 141:849 (1988).PubMedGoogle Scholar
  43. 43.
    G. S. Firestein, W. D. Roeder, J. A. Laxer, K. S. Townsend, C. T. Weaver, J. T. Hom, J. Linton, B. E. Torbett, and A. L. Glasebrook, A new murine T cell subset with an unrestricted cytokine profile, J. Immunol. 143:578 (1989).Google Scholar
  44. 44.
    H. K. Gershenfeld and I. L. Weissman, Cloning of a cDNA for a T cell-specific serine protease from a cytotoxic T lymphocyte, Science 232:854 (1986).PubMedCrossRefGoogle Scholar
  45. 45.
    C. L. Lobe, B. B. Finlay, W. Paranchych, V. H. Paetkau, and R. C. Bleackley, Novel serine proteases encoded by two cytotoxic T lymphocyte-specific genes, Science 232:858 (1986).PubMedCrossRefGoogle Scholar
  46. 46.
    J.-F. Brunet, M. Dosseto, F. Denizo, M.-G. Mattei, W. R. Clark, T. M. Maqqi, and P. Golstein, The inducible cytotoxic T-lymphocyte-associated gene transcript CTLA-1 sequence and gene localization to mouse chromosome 14, Nature 322:268 (1986).PubMedCrossRefGoogle Scholar
  47. 47.
    D. Masson and J. Tschopp, A family of serine esterases in lytic granules of cytolytic T lymphocytes, Cell 49:679 (1987).PubMedCrossRefGoogle Scholar
  48. 48.
    T. J. Novak, P. M. White, and E. V. Rothenberg, Regulatory anatomy of the murine interleukin-2 gene, Nucl. Acids Res. 18 (1990, in press).Google Scholar
  49. 49.
    T. J. Novak and E. V. Rothenberg, cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells (1990, submitted for publication).Google Scholar
  50. 50.
    J. D. Dignam, R. M. Lebowitz, and R. G. Roeder, Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei, Nucl. Acids Res. 11:1475 (1983).PubMedCrossRefGoogle Scholar
  51. 51.
    J.-P. Shaw, P.-J. Utz, D. B. Durand, J. J. Toole, E. A. Emmel, and G. R. Crabtree, Identification of a putative regulator of early T-cell activation genes, Science 241:202 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Ellen V. Rothenberg
    • 1
  • Dan Chen
    • 1
  • Rochelle A. Diamond
    • 1
  • Mariam Dohadwala
    • 1
  • Thomas J. Novak
    • 1
  • Patricia M. White
    • 1
  • Julia A. Yang-Snyder
    • 1
  1. 1.Division of BiologyCalifornia Institute of TechnologyPasadenaUSA

Personalised recommendations