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Lamina propria T cell activation: role of the costimulatory molecule CD2 and its cytoplasmic tail for the regulation of proliferation and apoptosis

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background/aims

Accumulation of T lymphocytes in the gut is a hallmark of inflammatory bowel disease probably caused by insufficient T cell apoptosis. Activated peripheral T cells, or “resting” lamina propria T lymphocytes (LPLs), are highly susceptible to apoptosis induction, e.g., using the mitogenic anti-CD2 monoclonal antibody (mAb) pair T112+3. It is, however, unknown how CD2-mediated LPL apoptosis is related to proliferation and whether the whole CD2 molecule is required for apoptosis induction.

Materials and methods

Mapping of anti-CD2 mAb was performed using erythrocyte rosetting assays and cross-blocking enzyme-linked immunosorbent assay (ELISA). Lamina propria mononuclear cells (LPMNCs) or phytohemagglutinin (PHA) blasts were stimulated with a panel of 18 anti-CD2 mAbs followed by apoptosis analysis [Annexin V expression on propidium iodide (PI)-negative cells, 4c6-diamidino-2-phenylindole·2HCl (DAPI) staining]. Proliferation was measured by [3H]-thymidine incorporation. For structural analysis, EL4 cells were used which were transfected with human CD2 (wild type (WT), cytoplasmic-deficient, cytoplasmic CD28). Sorting was performed employing standard techniques

Results

All three mitogenic anti-CD2 mAb pairs induced apoptosis of LPMNC and PHA blasts. Two out of four submitogenic anti-CD2 mAb, AICD2.M3, and ICRFCD2.3 lead to LPMNC proliferation but no apoptosis. Importantly, apoptosis was also detected in cytoplasmic-deficient CD2 tg or CD2/CD2/CD28 tg EL4 cells. Sorted CD45high huCD2 WT EL4 had higher apoptosis rates compared to WT huCD2tg EL4 cells

Conclusion

LPMNC apoptosis induction via CD2 is always associated with proliferation, although proliferation is not necessarily associated with apoptosis. The cytoplasmic tail of CD2 is not required, and CD45 appears to transmit apoptotic signals entering the T cell via CD2.

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Abbreviations

LPL-T:

lamina propria T lymphocytes

LPMNCs:

lamina propria mononuclear

IEL:

intraepithelial lymphocytes

TCR:

T cell receptor

References

  1. Zeitz M, Quinn TC, Graeff AS, James SP (1988) Mucosal T cells provide helper function but do not proliferate when stimulated by specific antigen in lymphogranuloma venereum proctitis in nonhuman primates. Gastroenterology 94:353–366

    PubMed  CAS  Google Scholar 

  2. Pirzer UC, Schürmann G, Post S, Betzler M, Meuer SC (1990) Differential responsiveness to CD3-Ti vs. CD2-dependent activation of human intestinal T lymphocytes. Eur J Immunol 20:2339–2342

    Article  PubMed  CAS  Google Scholar 

  3. Mattapallil JJ, Reay E, Dandekar S (2000) An early expansion of CD8alphabeta T cells, but depletion of resident CD8alphaalpha T cells, occurs in the intestinal epithelium during primary simian immunodeficiency virus infection. AIDS 14:637–646

    Article  PubMed  CAS  Google Scholar 

  4. Mittrucker HW, Kohler A, Mak TW, Kaufmann SH (1999) Critical role of CD28 in protective immunity against Salmonella typhimurium. J Immunol 163:6769–6776

    PubMed  CAS  Google Scholar 

  5. Mittrucker HW, Kursar M, Kohler A, Hurwitz R, Kaufmann SH (2001) Role of CD28 for the generation and expansion of antigen-specific CD8(+) T lymphocytes during infection with Listeria monocytogenes. J Immunol 167:5620–5627

    PubMed  CAS  Google Scholar 

  6. Boirivant M, Pica R, DeMaria R, Testi R, Pallone F, Strober W (1996) Stimulated human lamina propria T cells manifest enhanced Fas- mediated apoptosis. J Clin Invest 98:2616–2622

    Article  PubMed  CAS  Google Scholar 

  7. Ina K, Itoh J, Fukushima K, Kusugami K, Yamaguchi T, Kyokane K, Imada A, Binion DG, Musso A, West GA, Dobrea GM, McCormick TS, Lapetina EG, Levine AD, Ottaway CA, Fiocchi C (1999) Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol 163:1081–1090

    PubMed  CAS  Google Scholar 

  8. Wesselborg S, Prufer U, Wild M, Schraven B, Meuer SC, Kabelitz D (1993) Triggering via the alternative CD2 pathway induces apoptosis in activated human T lymphocytes. Eur J Immunol 23:2707–2710

    Article  PubMed  CAS  Google Scholar 

  9. Wesselborg S, Janssen O, Kabelitz D (1993) Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol 150:4338–4345

    PubMed  CAS  Google Scholar 

  10. Schieferdecker HL, Ullrich R, Weiss-Breckwoldt AN, Schwarting R, Stein H, Riecken EO, Zeitz M (1990) The HML-1 antigen of intestinal lymphocytes is an activation antigen. J Immunol 144:2541–2549

    PubMed  CAS  Google Scholar 

  11. Sturm A, Mohr S, Fiocchi C (2002) Critical role of caspases in the regulation of apoptosis and proliferation of mucosal T cells. Gastroenterology 122:1334–1345

    Article  PubMed  CAS  Google Scholar 

  12. Rouleau M, Bernard A, Lantz O, Vernant JP, Charpentier B, Senik A (1993) Apoptosis of activated CD8+/CD57+ T cells is induced by some combinations of anti-CD2 mAb. J Immunol 151:3547–3556

    PubMed  CAS  Google Scholar 

  13. Dumont C, Durrbach A, Bidere N, Rouleau M, Kroemer G, Bernard G, Hirsch F, Charpentier B, Susin SA, Senik A (2000) Caspase-independent commitment phase to apoptosis in activated blood T lymphocytes: reversibility at low apoptotic insult. Blood 96:1030–1038

    PubMed  CAS  Google Scholar 

  14. Rouleau M, Mollereau B, Bernard A, Metivier D, Rosenthal Allieri MA, Charpentier B, Senik A (1994) Mitogenic CD2 monoclonal antibody pairs predispose peripheral T cells to undergo apoptosis on interaction with a third CD2 monoclonal antibody. J Immunol 152:4861–4872

    PubMed  CAS  Google Scholar 

  15. Mollereau B, Deckert M, Deas O, Rieux Laucat F, Hirsch F, Bernard A, Fischer A, Lynch DH, Charpentier B, Le Deist F, Senik A (1996) CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation. J Immunol 156:3184–3190

    PubMed  CAS  Google Scholar 

  16. Guyot DJ, Trask OJ, Andrews JM, Newbound GC, Lairmore MD (1996) Stimulation of the CD2 receptor pathway induces apoptosis in human T lymphotropic virus type I-infected cell lines. J Acquir Immune Defic Syndr Human Retrovirol 11:317–325

    CAS  Google Scholar 

  17. Dumont C, Deas O, Mollereau B, Hebib C, Giovino-Barry V, Bernard A, Hirsch F, Charpentier B, Senik A (1998) Potent apoptotic signaling and subsequent unresponsiveness induced by a single CD2 mAb (BTI-322) in activated human peripheral T cells. J Immunol 160:3797–3804

    PubMed  CAS  Google Scholar 

  18. Fournel S, Robinet E, Bonnefoy-Berard N, Assossou O, Flacher M, Waldmann H, Bismuth G, Revillard JP (1998) A noncomitogenic CD2R monoclonal antibody induces apoptosis of activated T cells by a CD95/CD95-l-dependent pathway. J Immunol 160:4313–4321

    PubMed  CAS  Google Scholar 

  19. Deas O, Dumont C, MacFarlane M, Rouleau M, Hebib C, Harper F, Hirsch F, Charpentier B, Cohen GM, Senik A (1998) Caspase-independent cell death induced by anti-CD2 or staurosporine in activated human peripheral T lymphocytes. J Immunol 161:3375–3383

    PubMed  CAS  Google Scholar 

  20. Wild MK, Cambiaggi A, Brown MH, Davies EA, Ohno H, Saito T, van der Merwe PA (1999) Dependence of T cell antigen recognition on the dimensions of an accessory receptor–ligand complex. J Exp Med 190:31–41

    Article  PubMed  CAS  Google Scholar 

  21. Verhagen AM, Schraven B, Wild M, Wallich R, Meuer SC (1996) Differential interaction of the CD2 extracellular and intracellular domains with the tyrosine phosphatase CD45 and the zeta chain of the TCR/CD3/zeta complex. Eur J Immunol 26:2841–2849

    Article  PubMed  CAS  Google Scholar 

  22. Peterson A, Seed B (1987) Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2). Nature 329:842–846

    Article  PubMed  CAS  Google Scholar 

  23. Somoza C, Driscoll PC, Cyster JG, Williams AF (1993) Mutational analysis of the CD2/CD58 interaction: the binding site for CD58 lies on one face of the first domain of human CD2. J Exp Med 178:549–558

    Article  PubMed  CAS  Google Scholar 

  24. Arulanandam AR, Withka JM, Wyss DF, Wagner G, Kister A, Pallai P, Recny MA, Reinherz EL (1993) The CD58 (LFA-3) binding site is a localized and highly charged surface area on the AGFCC′C″ face of the human CD2 adhesion domain. Proc Natl Acad Sci U S A 90:11613–11617

    Article  PubMed  CAS  Google Scholar 

  25. Ikemizu S, Sparks LM, van der Merwe PA, Harlos K, Stuart DI, Jones EY, Davis SJ (1999) Crystal structure of the CD2-binding domain of CD58 (lymphocyte function-associated antigen 3) at 1.8-A resolution. Proc Natl Acad Sci U S A 96:4289–4294

    Article  PubMed  CAS  Google Scholar 

  26. Fleischer B (1987) A novel pathway of human T cell activation via a 103 kD T cell activation antigen. J Immunol 138:1346–1350

    PubMed  CAS  Google Scholar 

  27. Schwarz M, Bohuslav J, Majdic O, Stockinger H, Knapp W, Holter W (1995) Identification of the TS2/18-recognized epitope on the CD2 molecule as a target for suppression of T cell cytokine synthesis. J Immunol 154:5813–5820

    PubMed  CAS  Google Scholar 

  28. Wild MK, Verhagen AM, Meuer SC, Schraven B (1997) The receptor function of CD2 in human CD2 transgenic mice is based on highly conserved associations with signal transduction molecules. Cell Immunol 180:168–175

    Article  PubMed  CAS  Google Scholar 

  29. Altin JG, Pagler EB, Parish CR (1994) Evidence for cell surface association of CD2 and LFA-1 (CD11a/CD18) on T lymphocytes. Eur J Immunol 24:450–457

    Article  PubMed  CAS  Google Scholar 

  30. Carmo AM, Castro MA, Arosa FA (1999) CD2 and CD3 associate independently with CD5 and differentially regulate signaling through CD5 in Jurkat T cells. J Immunol 163:4238–4245

    PubMed  CAS  Google Scholar 

  31. Castro MA, Tavares PA, Almeida MS, Nunes RJ, Wright MD, Mason D, Moreira A, Carmo AM (2002) CD2 physically associates with CD5 in rat T lymphocytes with the involvement of both extracellular and intracellular domains. Eur J Immunol 32:1509–1518

    Article  PubMed  CAS  Google Scholar 

  32. Altevogt P, Schreck J, Schraven B, Meuer S, Schirrmacher V, Mitsch A (1990) Association of CD2 and T200 (CD45) in mouse T lymphocytes. Int Immunol 2:353–360

    Article  PubMed  CAS  Google Scholar 

  33. Schraven B, Samstag Y, Altevogt P, Meuer SC (1990) Association of CD2 and CD45 on human T lymphocytes. Nature 345:71–74

    Article  PubMed  CAS  Google Scholar 

  34. Donovan JA, Goldman FD, Koretzky GA (1994) Restoration of CD2-mediated signaling by a chimeric membrane protein including the cytoplasmic sequence of CD45. Hum Immunol 40:123–130

    Article  PubMed  CAS  Google Scholar 

  35. van der Merwe PA, Davis SJ, Shaw AS, Dustin ML (2000) Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin Immunol 12:5–21

    Article  Google Scholar 

  36. van der Merwe PA (2002) Formation and function of the immunological synapse. Curr Opin Immunol 14:293–298

    Article  PubMed  Google Scholar 

  37. van der Merwe PA, Davis SJ (2003) Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 21:659–684

    Article  PubMed  Google Scholar 

  38. Davis SJ, Ikemizu S, Evans EJ, Fugger L, Bakker TR, van der Merwe PA (2003) The nature of molecular recognition by T cells. Nat Immunol 4:217–224

    Article  PubMed  CAS  Google Scholar 

  39. Zeitz M, Greene WC, Peffer NJ, James SP (1988) Lymphocytes isolated from the intestinal lamina propria of normal nonhuman primates have increased expression of genes associated with T-cell activation. Gastroenterology 94:647–655

    PubMed  CAS  Google Scholar 

  40. Schieferdecker HL, Ullrich R, Hirseland H, Zeitz M (1992) T cell differentiation antigens on lymphocytes in the human intestinal lamina propria. J Immunol 149:2816–2822

    PubMed  CAS  Google Scholar 

  41. Rosenthal Allieri MA, Ticchioni M, Deckert M, Breittmayer JP, Rochet N, Rouleaux M, Senik A, Bernard A (1995) Monocyte-independent T cell activation by simultaneous binding of three CD2 monoclonal antibodies (D66 + T11.1 + GT2). Cell Immunol 163:88–95

    Article  PubMed  CAS  Google Scholar 

  42. Bierer BE, Bogart RE, Burakoff SJ (1990) Partial deletions of the cytoplasmic domain of CD2 result in a partial defect in signal transduction. J Immunol 144:785–789

    PubMed  CAS  Google Scholar 

  43. Hahn WC, Rosenstein Y, Calvo V, Burakoff SJ, Bierer BE (1992) A distinct cytoplasmic domain of CD2 regulates ligand avidity and T-cell responsiveness to antigen. Proc Natl Acad Sci U S A 89:7179–7183

    Article  PubMed  CAS  Google Scholar 

  44. Yang H, Reinherz EL (2001) Dynamic recruitment of human CD2 into lipid rafts. Linkage to T cell signal transduction. J Biol Chem 276:18775–18785

    Article  PubMed  CAS  Google Scholar 

  45. Ishii T, Ohnuma K, Murakami A, Takasawa N, Kobayashi S, Dang NH, Schlossman SF, Morimoto C (2001) CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO. Proc Natl Acad Sci U S A 98:12138–12143

    Article  PubMed  CAS  Google Scholar 

  46. Klaus SJ, Sidorenko SP, Clark EA (1996) CD45 ligation induces programmed cell death in T and B lymphocytes. J Immunol 156:2743–2753

    PubMed  CAS  Google Scholar 

  47. Fortin M, Steff AM, Felberg J, Ding I, Schraven B, Johnson P, Hugo P (2002) Apoptosis mediated through CD45 is independent of its phosphatase activity and association with leukocyte phosphatase-associated phosphoprotein. J Immunol 168:6084–6089

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank S.C. Meuer, Heidelberg, Germany, for various hybridoma cell lines. We thank A. Bernard, Nice, France, and B. Fleischer, Hamburg, Germany, for providing purified anti-CD2 mAb or hybridoma cell line, respectively. The expert technical assistance of B. Herrmann, Homburg, is acknowledged. B. Siegmund, Berlin, and M.W. Hoffmann, Hannover, gave important comments on the manuscript. This work was supported by DFG grant Ho 1561/3–5 to J.C.H. and M.Z. and grant B3 of the SFB 633 by the DFG. In addition, J.C.H. and M.Z. are supported by the German competence network IBD (DLR/BMBF).

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Authors and Affiliations

  1. Innere Medizin II, Medizinische Klinik, Universitätskliniken des Saarlandes, 66421, Homburg/Saar, Germany

    Sven Henschke, Martin Zeitz & Jörg C. Hoffmann

  2. Medizinische Klinik I mit Schwerpunkt Gastroenterologie/Infektiologie/Rheumatologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200, Berlin, Germany

    Nina N. Pawlowski, Martin Zeitz & Jörg C. Hoffmann

  3. Max Planck Institute for Molecular Biomedicine/Institute of Cell Biology, ZMBE, University of Münster, Von-Esmarch-Str. 56, 48149, Muenster, Germany

    Martin K. Wild

  4. Chirurgische Klinik I, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200, Berlin, Germany

    Anton J. Kroesen

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  1. Sven Henschke
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Correspondence to Jörg C. Hoffmann.

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Henschke, S., Pawlowski, N.N., Wild, M.K. et al. Lamina propria T cell activation: role of the costimulatory molecule CD2 and its cytoplasmic tail for the regulation of proliferation and apoptosis. Int J Colorectal Dis 21, 321–331 (2006). https://doi.org/10.1007/s00384-005-0016-2

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