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. 1996 Dec 1;98(11):2616–2622. doi: 10.1172/JCI119082

Stimulated human lamina propria T cells manifest enhanced Fas-mediated apoptosis.

M Boirivant 1, R Pica 1, R DeMaria 1, R Testi 1, F Pallone 1, W Strober 1
PMCID: PMC507721  PMID: 8958226

Abstract

Lamina propria (LP) T cells respond poorly to a proliferative stimulus delivered via TCR/CD3 pathway, but retain considerable ability to respond to a stimulus delivered via CD2 costimulatory or accessory pathway. In the present study, we showed first that unstimulated LP T cells, as compared to unstimulated peripheral blood (PB) T cells, exhibit an increased level of apoptosis which is further increased following CD2 pathway stimulation, but not following via TCR/CD3 pathway stimulation. We next showed that IL-2 had a sparing effect on apoptosis of unstimulated LP T cells in that IL-2 decreased and anti-IL-2 increased apoptosis of these cells; in contrast, IL-2 had no effect on apoptosis of CD2-pathway stimulated cells. Finally, we showed that increased apoptosis of LP T cells induced by CD2-pathway stimulation is inhibited when Fas antigen is blocked by a nonstimulatory anti-Fas antibody. These studies suggest that LP T cells are characterized by increased susceptibility to Fas-mediated apoptosis most due to a downstream change in the Fas signaling pathway. Given that IFN-gamma secretion is significantly increased in LP T cells in which apoptosis is inhibited, this feature of LP T cells may represent a mechanism of regulating detrimental immune responses in the mucosal environment.

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Selected References

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  1. Alderson M. R., Armitage R. J., Maraskovsky E., Tough T. W., Roux E., Schooley K., Ramsdell F., Lynch D. H. Fas transduces activation signals in normal human T lymphocytes. J Exp Med. 1993 Dec 1;178(6):2231–2235. doi: 10.1084/jem.178.6.2231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alderson M. R., Tough T. W., Davis-Smith T., Braddy S., Falk B., Schooley K. A., Goodwin R. G., Smith C. A., Ramsdell F., Lynch D. H. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71–77. doi: 10.1084/jem.181.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beverly B., Kang S. M., Lenardo M. J., Schwartz R. H. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol. 1992 Jun;4(6):661–671. doi: 10.1093/intimm/4.6.661. [DOI] [PubMed] [Google Scholar]
  4. Boirivant M., Fuss I., Fiocchi C., Klein J. S., Strong S. A., Strober W. Hypoproliferative human lamina propria T cells retain the capacity to secrete lymphokines when stimulated via CD2/CD28 pathways. Proc Assoc Am Physicians. 1996 Jan;108(1):55–67. [PubMed] [Google Scholar]
  5. Boussiotis V. A., Freeman G. J., Griffin J. D., Gray G. S., Gribben J. G., Nadler L. M. CD2 is involved in maintenance and reversal of human alloantigen-specific clonal anergy. J Exp Med. 1994 Nov 1;180(5):1665–1673. doi: 10.1084/jem.180.5.1665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brandtzaeg P., Halstensen T. S., Kett K., Krajci P., Kvale D., Rognum T. O., Scott H., Sollid L. M. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology. 1989 Dec;97(6):1562–1584. doi: 10.1016/0016-5085(89)90406-x. [DOI] [PubMed] [Google Scholar]
  7. Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
  8. Bull D. M., Bookman M. A. Isolation and functional characterization of human intestinal mucosal lymphoid cells. J Clin Invest. 1977 May;59(5):966–974. doi: 10.1172/JCI108719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cifone M. G., De Maria R., Roncaioli P., Rippo M. R., Azuma M., Lanier L. L., Santoni A., Testi R. Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J Exp Med. 1994 Oct 1;180(4):1547–1552. doi: 10.1084/jem.180.4.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. De Maria R., Boirivant M., Cifone M. G., Roncaioli P., Hahne M., Tschopp J., Pallone F., Santoni A., Testi R. Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation. J Clin Invest. 1996 Jan 15;97(2):316–322. doi: 10.1172/JCI118418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
  12. Fuss I. J., Neurath M., Boirivant M., Klein J. S., de la Motte C., Strong S. A., Fiocchi C., Strober W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996 Aug 1;157(3):1261–1270. [PubMed] [Google Scholar]
  13. Galelli A., Delcourt M., Wagner M. C., Peumans W., Truffa-Bachi P. Selective expansion followed by profound deletion of mature V beta 8.3+ T cells in vivo after exposure to the superantigenic lectin Urtica dioica agglutinin. J Immunol. 1995 Mar 15;154(6):2600–2611. [PubMed] [Google Scholar]
  14. Hernández-Caselles T., Martínez-Esparza M., Sancho D., Rubio G., Aparicio P. Interleukin-7 rescues human activated T lymphocytes from apoptosis induced by glucocorticoesteroids and regulates bcl-2 and CD25 expression. Hum Immunol. 1995 Jul;43(3):181–189. doi: 10.1016/0198-8859(94)00168-p. [DOI] [PubMed] [Google Scholar]
  15. Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
  16. Kabelitz D., Pohl T., Pechhold K. Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol Today. 1993 Jul;14(7):338–339. doi: 10.1016/0167-5699(93)90231-9. [DOI] [PubMed] [Google Scholar]
  17. Klas C., Debatin K. M., Jonker R. R., Krammer P. H. Activation interferes with the APO-1 pathway in mature human T cells. Int Immunol. 1993 Jun;5(6):625–630. doi: 10.1093/intimm/5.6.625. [DOI] [PubMed] [Google Scholar]
  18. Lenardo M. J. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. doi: 10.1038/353858a0. [DOI] [PubMed] [Google Scholar]
  19. Miyawaki T., Uehara T., Nibu R., Tsuji T., Yachie A., Yonehara S., Taniguchi N. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992 Dec 1;149(11):3753–3758. [PubMed] [Google Scholar]
  20. Pallone F., Fais S., Squarcia O., Biancone L., Pozzilli P., Boirivant M. Activation of peripheral blood and intestinal lamina propria lymphocytes in Crohn's disease. In vivo state of activation and in vitro response to stimulation as defined by the expression of early activation antigens. Gut. 1987 Jun;28(6):745–753. doi: 10.1136/gut.28.6.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Peters M. G., Secrist H., Anders K. R., Nash G. S., Rich S. R., MacDermott R. P. Normal human intestinal B lymphocytes. Increased activation compared with peripheral blood. J Clin Invest. 1989 Jun;83(6):1827–1833. doi: 10.1172/JCI114088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pirzer U. C., Schürmann G., Post S., Betzler M., Meuer S. C. Differential responsiveness to CD3-Ti vs. CD2-dependent activation of human intestinal T lymphocytes. Eur J Immunol. 1990 Oct;20(10):2339–2342. doi: 10.1002/eji.1830201025. [DOI] [PubMed] [Google Scholar]
  23. Qiao L., Schürmann G., Betzler M., Meuer S. C. Activation and signaling status of human lamina propria T lymphocytes. Gastroenterology. 1991 Dec;101(6):1529–1536. doi: 10.1016/0016-5085(91)90388-2. [DOI] [PubMed] [Google Scholar]
  24. Renno T., Hahne M., MacDonald H. R. Proliferation is a prerequisite for bacterial superantigen-induced T cell apoptosis in vivo. J Exp Med. 1995 Jun 1;181(6):2283–2287. doi: 10.1084/jem.181.6.2283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Savill J., Fadok V., Henson P., Haslett C. Phagocyte recognition of cells undergoing apoptosis. Immunol Today. 1993 Mar;14(3):131–136. doi: 10.1016/0167-5699(93)90215-7. [DOI] [PubMed] [Google Scholar]
  26. Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
  27. Targan S. R., Deem R. L., Liu M., Wang S., Nel A. Definition of a lamina propria T cell responsive state. Enhanced cytokine responsiveness of T cells stimulated through the CD2 pathway. J Immunol. 1995 Jan 15;154(2):664–675. [PubMed] [Google Scholar]
  28. Tartaglia L. A., Ayres T. M., Wong G. H., Goeddel D. V. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993 Sep 10;74(5):845–853. doi: 10.1016/0092-8674(93)90464-2. [DOI] [PubMed] [Google Scholar]
  29. Ucker D. S., Meyers J., Obermiller P. S. Activation-driven T cell death. II. Quantitative differences alone distinguish stimuli triggering nontransformed T cell proliferation or death. J Immunol. 1992 Sep 1;149(5):1583–1592. [PubMed] [Google Scholar]
  30. Watanabe M., Ueno Y., Yajima T., Iwao Y., Tsuchiya M., Ishikawa H., Aiso S., Hibi T., Ishii H. Interleukin 7 is produced by human intestinal epithelial cells and regulates the proliferation of intestinal mucosal lymphocytes. J Clin Invest. 1995 Jun;95(6):2945–2953. doi: 10.1172/JCI118002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wesselborg S., Janssen O., Kabelitz D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J Immunol. 1993 May 15;150(10):4338–4345. [PubMed] [Google Scholar]
  32. Zamai L., Falcieri E., Zauli G., Cataldi A., Vitale M. Optimal detection of apoptosis by flow cytometry depends on cell morphology. Cytometry. 1993 Nov;14(8):891–897. doi: 10.1002/cyto.990140807. [DOI] [PubMed] [Google Scholar]
  33. Zheng L., Fisher G., Miller R. E., Peschon J., Lynch D. H., Lenardo M. J. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995 Sep 28;377(6547):348–351. doi: 10.1038/377348a0. [DOI] [PubMed] [Google Scholar]

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