title: Apoptosis following interleukin-2 withdrawal from T cells: evidence for a regulatory role of CD18 (beta 2-integrin) molecules.
abstract: Following a successful immune response against invading microorganisms, the majority of activated T cells is eliminated, while a minor fraction survives as memory T cells. A decline in T lymphocyte growth factors such as interleukin-2 (IL-2) appears to play a role in the elimination of previously activated T cells. Thus, removal of IL-2 from proliferating T cells not only induces growth arrest, but triggers a massive cell death due to apoptosis. While the apoptotic response involves a series of well-described events, it remains less clear how apoptosis is regulated following IL-2 withdrawal. Here, we provide evidence that CD18 molecules (beta 2-integrins) play a regulatory role in the apoptotic response following removal of IL-2 from previously activated, antigen specific CD4+ T cell lines. Thus, CD18 mAb inhibited the apoptotic response to IL-2 deprivation, whereas mAb against other adhesion molecules (CD28, CD29, CD49d, CD80, CD86) did not. Secondly, IL-2 withdrawal resulted in a retarded apoptotic response in LFA-1 (CD11a/CD18) negative T cells obtained from a leukocyte adhesion deficiency (LAD) patient, as compared to LFA-1 positive T cell lines. Thirdly, co-culture of LFA-1 positive- and negative-T cells at different ratios induced apoptotic responses that were higher than expected, had the two lymphocyte populations not been interacting and significantly higher than that seen in pure LFA-1 negative T cells. Supernatants from LFA-1 positive T cell cultures undergoing apoptosis did not induce an enhanced apoptotic responses in LFA-1 negative T cells, and, reversely, culture supernatants from LFA-1 negative T cells did not rescue LFA-1 positive cells from undergoing apoptosis. The apoptotic response was partly blocked by IL-15, a newly identified T cell growth factor. Taken together, these findings suggest that CD18 molecules (beta 2-integrins) play a regulatory role in the apoptotic response following cytokine withdrawal, and that the regulation is mediated, at least partly, through T-T cell interactions. Thus, apoptotic death following IL-2 deprivation appears to be under "social" control by surrounding T cells.
authors.affiliation: Institute of Medical Anatomy, University of Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Röpke
authors.forename: P
authors.initials: P
authors.lastname: Gladstone
authors.forename: M
authors.initials: M
authors.lastname: Nielsen
authors.forename: N
authors.initials: N
authors.lastname: Borregaard
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
authors.forename: A
authors.initials: A
authors.lastname: Svejgaard
authors.forename: N
authors.initials: N
authors.lastname: Odum
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018821:CD18 Antigens / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007376:Interleukin-2 / Q000172:deficiency* / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D018821:CD18 Antigens; D007376:Interleukin-2; D007519:Isoantigens; D016169:Lymphocyte Function-Associated Antigen-1