TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs
Brygida Bisikirska, … , Jeffrey A. Bluestone, Kevan C. Herold
Brygida Bisikirska, … , Jeffrey A. Bluestone, Kevan C. Herold
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2904-2913. https://doi.org/10.1172/JCI23961.
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Research Article Immunology

TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs

Abstract

Modified anti-CD3 mAbs are emerging as a possible means of inducing immunologic tolerance in settings including transplantation and autoimmunity such as in type 1 diabetes. In a trial of a modified anti-CD3 mAb [hOKT3γ1(Ala-Ala)] in patients with type 1 diabetes, we identified clinical responders by an increase in the number of peripheral blood CD8+ cells following treatment with the mAb. Here we show that the anti-CD3 mAb caused activation of CD8+ T cells that was similar in vitro and in vivo and induced regulatory CD8+CD25+ T cells. These cells inhibited the responses of CD4+ cells to the mAb itself and to antigen. The regulatory CD8+CD25+ cells were CTLA4+ and Foxp3+ and required contact for inhibition. Foxp3 was also induced on CD8+ T cells in patients during mAb treatment, which suggests a potential mechanism of the anti-CD3 mAb immune modulatory effects involving induction of a subset of regulatory CD8+ T cells.

Authors

Brygida Bisikirska, John Colgan, Jeremy Luban, Jeffrey A. Bluestone, Kevan C. Herold

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Changes in CD4/CD8 T cell ratio in subjects with type 1 diabetes receivi...
Changes in CD4/CD8 T cell ratio in subjects with type 1 diabetes receiving hOKT3γ1(Ala-Ala) in relation to EBV status at study entry, and correlation between changes in CD4+ and CD8+ T cells in vitro during culture with anti-CD3 mAb and in vivo following treatment with anti-CD3 mAb. (A) The difference in the CD4/CD8 T cell ratio 3 months after treatment with hOKT3γ1(Ala-Ala) from the ratio before drug treatment in individuals who were EBV seropositive (n = 12) or seronegative (n = 7) at study entry was determined. The dark lines indicate the mean values for the group. A decrease in the CD4/CD8 T cell ratio (below the dotted line) occurred in both EBV-seropositive and -seronegative subjects. (B) PBMCs from patients with type 1 diabetes mellitus who received anti-CD3 mAb were studied 1.5–2 years after mAb treatment, at which time the changes in CD4/CD8 T cell ratio seen after mAb treatment had resolved. The patients were designated as clinical responders (filled circles) or nonresponders (open circles) based on their C-peptide responses at 12 months compared with baseline. The cells were cultured with hOKT3γ1(Ala-Ala), and the percentages of CD4+ and CD8+ T cells were determined after 6 days. The Pearson correlation coefficient was calculated to compare the ratio of CD4+/CD8+ T cells in vitro with the analysis of CD4+/CD8+ T cells in vivo 3 months after mAb treatment (8), and the level of significance was tested with correlation procedure SAS (r = 0.6; P = 0.024). The line indicates the relationship between the changes in vitro and in vivo [in vivo CD4/CD8 ratio = 0.174 + 0.865 (in vitro CD4/CD8 ratio)].