Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells

Miguel A. Medina, Jacob Couturier, Marsha L. Feske, Ashley E. Mahne, Mary Turner, Xiaoying Yu, Claudia A. Kozinetz, Aaron F. Orozco, Alexander T. Hutchison, Tor C. Savidge, John R. Rodgers, Dorothy E. Lewis

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Some human memory CD4+ T cells have cytotoxic functions best understood in the context of viral infections; however, their possible role in pathologic processes is understudied. The novel discovery that mitogenic CD28 antibodies induced proliferation and expansion of Tregs offered therapeutic promise for autoimmune disorders. However, the failed TGN1412 trial forced reassessment of this concept. As memory CD4+ T cells are known to produce toxic molecules, including granzyme B (GrzB) and FasL, we wondered whether mitogenic CD28 was able to induce these cytotoxic molecules. A commercially available mitogenic human CD28 mAb (clone ANC28.1) was used to determine whether mitogenic CD28 induces cytotoxic function from human memory CD4+ T cells. We found that stimulation of memory CD4+ T cells by ANC28.1, as well as by conventional costimulation (CD3/CD28 mAb), robustly induced enzymatically active GrzB, along with increased surface expression of FasL. These functional phenotypes were induced in association with increased expression of T cell activation markers CD69 and CD25, and elimination of target cells by ANC28.1-acti-vated memory CD4+ T cells involved both GrzB and FasL. Additionally, ANC28.1-activated memory CD4+ T cells caused disruption of epithelial cell monolayer integrity, which was partially mediated by GrzB. These findings reveal functions of memory CD4+ T cells previously unknown to be induced by mitogenic CD28, and suggest that these pathogenic mechanisms may have been responsible for some of the widespread tissue destruction that occurred in the TGN1412 trial recipients.

Original languageEnglish (US)
Pages (from-to)759-771
Number of pages13
JournalJournal of Leukocyte Biology
Volume91
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Fingerprint

Granzymes
Fas Ligand Protein
T-Lymphocytes
Poisons
Virus Diseases
Pathologic Processes
Clone Cells
Epithelial Cells
Phenotype
Antibodies

Keywords

  • ANC28.1
  • Apoptosis
  • Costimulation
  • Superagonistic CD28
  • TGN1412

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

Cite this

Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells. / Medina, Miguel A.; Couturier, Jacob; Feske, Marsha L.; Mahne, Ashley E.; Turner, Mary; Yu, Xiaoying; Kozinetz, Claudia A.; Orozco, Aaron F.; Hutchison, Alexander T.; Savidge, Tor C.; Rodgers, John R.; Lewis, Dorothy E.

In: Journal of Leukocyte Biology, Vol. 91, No. 5, 05.2012, p. 759-771.

Research output: Contribution to journalArticle

Medina, MA, Couturier, J, Feske, ML, Mahne, AE, Turner, M, Yu, X, Kozinetz, CA, Orozco, AF, Hutchison, AT, Savidge, TC, Rodgers, JR & Lewis, DE 2012, 'Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells', Journal of Leukocyte Biology, vol. 91, no. 5, pp. 759-771. https://doi.org/10.1189/jlb.0511264
Medina, Miguel A. ; Couturier, Jacob ; Feske, Marsha L. ; Mahne, Ashley E. ; Turner, Mary ; Yu, Xiaoying ; Kozinetz, Claudia A. ; Orozco, Aaron F. ; Hutchison, Alexander T. ; Savidge, Tor C. ; Rodgers, John R. ; Lewis, Dorothy E. / Granzyme B- and Fas ligand-mediated cytotoxic function induced by mitogenic CD28 stimulation of human memory CD4+ T cells. In: Journal of Leukocyte Biology. 2012 ; Vol. 91, No. 5. pp. 759-771.
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AU - Mahne, Ashley E.

AU - Turner, Mary

AU - Yu, Xiaoying

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AU - Orozco, Aaron F.

AU - Hutchison, Alexander T.

AU - Savidge, Tor C.

AU - Rodgers, John R.

AU - Lewis, Dorothy E.

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