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PMID: 7693849 Published · ppublish English Journal Article

In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions.

The Journal of experimental medicine ·Vol. 178 ·No. 5 ·1993-11-01 ·Pages 1555-65

Van den Eertwegh AJ, Noelle RJ, Roy M, Shepherd DM, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E

Abstract

T-B cell interactions have a central role in the development of antibody responses. Upon activation, T helper (Th) cells express the ligand for CD40, gp39, which is essential for Th cell-dependent B cell activation. The cytokines produced by activated Th cells have a regulatory role in B cell differentiation. In this study, we investigated, using immunohistochemical techniques, the in vivo time course and localization of gp39 expression and cytokine production in relation to the specific antibody production. Both the immunization with keyhole limpet hemocyanin (KLH), a thymus-dependent (TD) antigen, and trinitrophenyl (TNP)-Ficoll, a thymus-independent type 2 (TI-2) antigen, induced Th cells to express gp39. The expression of gp39 was restricted to Th cells in the outer periarteriolar lymphocyte sheaths (outer-PALS) and around the terminal arterioles (TA). Incidentally, gp39+ Th cells were found in the corona of follicles, whereas gp39+ cells were never found in the germinal centers or marginal zones of the spleen. Maximum frequencies of gp39+ cells were observed 3 and 4 d after primary and secondary immunization with KLH. After injection of TNP-Ficoll, a marked increase in gp39+ cells was observed, confirming previous observations that activated T cells are involved in TI-2 antibody responses. Analysis of the in vivo cytokine production revealed that interleukin 2 (IL-2)-, IL-4- and interferon gamma (IFN-gamma)-producing cells (IFN-gamma-PC) developed according to similar kinetics as observed for gp39+ cells. IL-2-PC and IL-4-PC were present in higher frequencies as were IFN-gamma-PC in the immune response against TNP-KLH. Double staining experiments revealed gp39+ Th cells producing IL-2, IL-4, or IFN-gamma, suggesting that these cells were involved in both the initial activation as well as the differentiation process of B cells into antibody-forming cells. Dual immunohistochemical analysis revealed gp39+ T cells and cytokine-PC in close proximity to antigen-specific, antibody-forming B cells. In conclusion, this study shows that in vivo gp39 is expressed on activated Th cells after immunization with TD and TI-2 antigens. Furthermore, the time course and compartmentalization of gp39+ expression, cytokine production and antibody formation after immunization suggest that cognate T-B cell interactions and T cell-regulated B cell differentiation occur in the outer-PALS and around the TA of the spleen.

MeSH Terms
Animals Antibodies, Monoclonal Antibody Formation Antigens/immunology Antigens, CD/metabolism Antigens, Differentiation, B-Lymphocyte/metabolism B-Lymphocytes/immunology CD40 Antigens CD40 Ligand Hemocyanins/immunology Immunization Immunohistochemistry Kinetics Lymphocyte Activation Membrane Glycoproteins/metabolism Mice Mice, Inbred C57BL Mice, Inbred CBA Mice, Inbred Strains Models, Biological Spleen/immunology T-Lymphocytes/immunology T-Lymphocytes, Helper-Inducer/immunology Thymus Gland/immunology
Chemicals
Antibodies, Monoclonal Antigens Antigens, CD Antigens, Differentiation, B-Lymphocyte CD40 Antigens Membrane Glycoproteins CD40 Ligand Hemocyanins keyhole-limpet hemocyanin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Van den Eertwegh A J
Department of Immunology and Medical Microbiology, TNO Medical Biological Laboratory, Rijswijk, The Netherlands.
Noelle R J
Roy M
Shepherd D M
Aruffo A
Ledbetter J A
Boersma W J
Claassen E
References (55)
55 references, click to expand
  1. Isolation and characterization of monoclonal antibodies directed to rat interferon-gamma.
    Lymphokine Res. 1989 Winter;8(4):439-49 PMID: 2478843
  2. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39.
    J Exp Med. 1993 Nov 1;178(5):1567-75 PMID: 7693850
  3. Separation of events mediating B cell proliferation and Ig production by using T cell membranes and lymphokines.
    J Immunol. 1990 Oct 1;145(7):2025-34 PMID: 2144543
  4. IL-4 directs the development of Th2-like helper effectors.
    J Immunol. 1990 Dec 1;145(11):3796-806 PMID: 2147202
  5. How does the helper T cell activate the resting B cell when it recognizes antigen on the B-cell surface?
    Res Immunol. 1990 May-Jun;141(4-5):405-7 PMID: 2148422
  6. B-cell proliferation and differentiation mediated by Th-cell membranes and lymphokines.
    Res Immunol. 1990 May-Jun;141(4-5):421-3 PMID: 2148426
  7. Cognate interactions between helper T cells and B cells. V. Reconstitution of T helper cell function using purified plasma membranes from activated Th1 and Th2 T helper cells and lymphokines.
    J Immunol. 1991 Feb 15;146(4):1118-24 PMID: 1704029
  8. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations.
    J Exp Med. 1991 May 1;173(5):1165-75 PMID: 1902502
  9. Regulation of lymphokine expression in T cell activation. I. Rapid loss of interleukin-specific RNA after removal of the stimulating signal.
    Eur J Immunol. 1991 Jul;21(7):1691-5 PMID: 2060578
  10. In vivo kinetics and characterization of IFN-gamma-producing cells during a thymus-independent immune response.
    J Immunol. 1991 Jul 15;147(2):439-46 PMID: 1906499
  11. Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB- helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma.
    J Exp Med. 1991 Sep 1;174(3):547-59 PMID: 1678774
  12. Germinal center T cells are distinct helper-inducer T cells.
    Hum Immunol. 1991 May;31(1):67-75 PMID: 1715336
  13. Membranes from both Th1 and Th2 T cell clones stimulate B cell proliferation and prepare B cells for lymphokine-induced differentiation to secrete Ig.
    J Immunol. 1991 Dec 1;147(11):3696-702 PMID: 1834744
  14. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development.
    Immunol Rev. 1991 Oct;123:115-44 PMID: 1684776
  15. Complement-mediated follicular localization of T-independent type-2 antigens: the role of marginal zone macrophages revisited.
    Eur J Immunol. 1992 Mar;22(3):719-26 PMID: 1547818
  16. Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help).
    J Exp Med. 1992 Apr 1;175(4):1091-101 PMID: 1348081
  17. Induction of IgG3 secretion by interferon gamma: a model for T cell-independent class switching in response to T cell-independent type 2 antigens.
    J Exp Med. 1992 May 1;175(5):1367-71 PMID: 1373759
  18. Signals involved in germinal center reactions.
    Immunol Rev. 1992 Apr;126:63-76 PMID: 1597321
  19. New immunoenzyme-cytochemical stainings for the in situ detection of epitope specificity and isotype of antibody forming B cells in experimental and natural (auto) immune responses in animals and man.
    J Immunol Methods. 1992 Jun 24;150(1-2):207-16 PMID: 1377214
  20. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells.
    Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550-4 PMID: 1378631
  21. Immunological functions and in vivo cell-cell interactions of T cells in the spleen.
    Crit Rev Immunol. 1992;11(6):337-80 PMID: 1388710
  22. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.
    EMBO J. 1992 Dec;11(12):4313-21 PMID: 1385114
  23. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help.
    J Immunol. 1992 Dec 15;149(12):3817-26 PMID: 1281189
  24. Cytokine expression by germinal center cells.
    J Immunol. 1993 Jan 1;150(1):39-47 PMID: 7678034
  25. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.
    Cell. 1993 Jan 29;72(2):291-300 PMID: 7678782
  26. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.
    Nature. 1993 Feb 11;361(6412):539-41 PMID: 7679206
  27. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM.
    Nature. 1993 Feb 11;361(6412):541-3 PMID: 8094231
  28. Ia-antigen-T-cell interactions for a thymus-independent antigen composed of D amino acids.
    Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):994-8 PMID: 8381541
  29. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.
    Science. 1993 Feb 12;259(5097):990-3 PMID: 7679801
  30. Immunohistochemical detection of co-localizing cytokine and antibody producing cells in the extrafollicular area of human palatine tonsils.
    Clin Exp Immunol. 1993 Aug;93(2):223-8 PMID: 8348748
  31. A comparative study on the preparation of immunoglobulin-galactosidase conjugates.
    J Histochem Cytochem. 1981 Nov;29(11):1273-80 PMID: 6798103
  32. Activation of antigen-enriched B cells. II. Role of linked recognition in B cell proliferation to thymus-dependent antigens.
    J Immunol. 1983 Feb;130(2):614-8 PMID: 6600245
  33. A requirement for nonspecific T cell factors in antibody responses to "T cell independent" antigens.
    J Immunol. 1983 Feb;130(2):781-4 PMID: 6336770
  34. T cell dependence and factor reconstitution of in vitro antibody responses to TNP-B. Abortus and TNP-Ficoll: restoration of depleted responses with chromatographed fractions of a T cell-derived factor.
    J Immunol. 1983 Aug;131(2):633-7 PMID: 6408185
  35. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule.
    J Immunol. 1983 Nov;131(5):2445-51 PMID: 6415170
  36. Clustering of dendritic cells, helper T lymphocytes, and histocompatible B cells during primary antibody responses in vitro.
    J Exp Med. 1984 Sep 1;160(3):858-76 PMID: 6206192
  37. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens.
    Immunol Rev. 1979;47:63-90 PMID: 398327
  38. Role of T lymphocytes in the response to TNP-AECM-Ficoll.
    J Immunol. 1980 Sep;125(3):1066-70 PMID: 6774013
  39. Monoclonal antibodies specific for rat IgG1, IgG2a, and IgG2b subclasses, and kappa chain monotypic and allotypic determinants: reagents for use with rat monoclonal antibodies.
    Hybridoma. 1982;1(3):257-73 PMID: 6208128
  40. Monoclonal helper T cells induce B cell responses to T-independent antigens: antigen-specific T cells are directly stimulated by activated B cells in the absence of antigen.
    J Immunol. 1985 Jan;134(1):86-90 PMID: 3155473
  41. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1.
    Nature. 1985 May 23-29;315(6017):333-6 PMID: 2582266
  42. Protein-specific helper T-lymphocyte formation initiated by dendritic cells.
    Science. 1985 Aug 2;229(4712):475-9 PMID: 3160115
  43. Localization of the E1B proteins of adenovirus 5 in transformed cells, as revealed by interaction with monoclonal antibodies.
    Virology. 1985 Apr 15;142(1):44-58 PMID: 2932843
  44. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.
    J Immunol. 1986 Apr 1;136(7):2348-57 PMID: 2419430
  45. Influence of carriers on the development and localization of anti-trinitrophenyl antibody-forming cells in the murine spleen.
    Eur J Immunol. 1986 Mar;16(3):271-6 PMID: 3514239
  46. Influence of carriers on the development and localization of anti-2,4,6-trinitrophenyl (TNP) antibody-forming cells in the murine spleen. II. Suppressed antibody response to TNP-Ficoll after elimination of marginal zone cells.
    Eur J Immunol. 1986 May;16(5):492-7 PMID: 2938975
  47. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production.
    Science. 1987 May 22;236(4804):944-7 PMID: 3107127
  48. Thymus-dependent antigenic stimulation of hapten-specific B lymphocytes.
    Immunol Rev. 1987 Oct;99:173-92 PMID: 2445657
  49. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors.
    Eur J Immunol. 1988 Jan;18(1):97-104 PMID: 2831066
  50. Frequencies of IL-2- and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations.
    J Immunol. 1988 May 15;140(10):3352-7 PMID: 3258881
  51. Regulation of IgG1 and IgE production by interleukin 4.
    Immunol Rev. 1988 Feb;102:51-75 PMID: 3284816
  52. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells.
    Nature. 1988 Jul 21;334(6179):255-8 PMID: 2456466
  53. Sequential double immunocytochemical staining for in situ identification of an auto-anti-allotype immune response in allotype-suppressed rabbits.
    J Histochem Cytochem. 1988 Dec;36(12):1455-61 PMID: 3057069
  54. Sudden appearance of anti-protein IgG1-forming cell precursors early during primary immunization.
    Proc Natl Acad Sci U S A. 1989 Jun;86(12):4679-83 PMID: 2786635
  55. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells.
    J Exp Med. 1990 Sep 1;172(3):921-9 PMID: 2117636
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.178.5.1555
Published
1993-11-01
Pages
1555-65
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191254
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.178.5.1555 PMC Full Text View journal details
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