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Mitogenic CD28 induces granzyme B and a cytokine storm in human TH1 cells
Author(s) -
Medina Miguel A.,
Martin Ashley,
Couturier Jacob,
Camell Christina,
Rodgers John,
Lewis Dorothy
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1072.17
Subject(s) - cd28 , cytokine , granzyme b , microbiology and biotechnology , ionomycin , jurkat cells , interleukin 21 , cytokine storm , t cell , biology , chemistry , immunology , immune system , medicine , intracellular , disease , covid-19 , infectious disease (medical specialty)
Phase I clinical trials with a humanized super‐agonistic CD28 monoclonal antibody resulted in multi‐organ failure with loss of lymphocytes in the periphery. We investigated the mechanism of mitogenic CD28 induced activation and cell death in T cells. Mitogenic but not conventional CD28 induced activation and apoptosis of the Jurkat but not H9 T cell line. In vitro polarized human T‐helper (Th1) cells were activated by mitogenic CD28, but unlike their TH2 counterparts, produced significant amounts of granzyme B (10 ug/ml) from 5 x 10 5 cells. Negatively selected human Th1 cells exhibit a Th1 like cytokine profile following PMA and ionomycin stimulation and express extracellular markers, CXCR3 and CCR5, a profile consistent with Th1 cells. Upon mitogenic CD28 stimulation more than half of the cells are activated and about 30% apoptotic similar to activation induced cell death seen after anti‐CD3 stimulation. Following mitogenic CD28 stimulation negatively selected TH1 cells produced a cytokine profile consistent with a cytokine storm. Therefore, activated inflammatory Th‐1 cells are potential producers of large quantities of granzyme B and inflammatory cytokines, which may be associated with multi‐organ failure in the phase I clinical trial. This study was supported by NIH grants R21‐AI054251, R37‐AI36682 and Center for AIDS Research grant P30 AI36211.