Regulatory functions of CD8+CD28– T cells in an autoimmune disease model
Nader Najafian, … , Mohamed H. Sayegh, Samia J. Khoury
Nader Najafian, … , Mohamed H. Sayegh, Samia J. Khoury
Published October 1, 2003
Citation Information: J Clin Invest. 2003;112(7):1037-1048. https://doi.org/10.1172/JCI17935.
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Article Autoimmunity

Regulatory functions of CD8+CD28– T cells in an autoimmune disease model

Abstract

CD8+ T cell depletion renders CD28-deficient mice susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, CD8–/–CD28–/– double-knockout mice are susceptible to EAE. These findings suggest a role for CD8+ T cells in the resistance of CD28-deficient mice to disease. Adoptive transfer of CD8+CD28– T cells into CD8–/– mice results in significant suppression of disease, while CD8+CD28+ T cells demonstrate no similar effect on the clinical course of EAE in the same recipients. In vitro, CD8+CD28– but not CD8+CD28+ T cells suppress IFN-γ production of myelin oligodendrocyte glycoprotein–specific CD4+ T cells. This suppression requires cell-to-cell contact and is dependent on the presence of APCs. APCs cocultured with CD8+CD28– T cells become less efficient in inducing a T cell–dependent immune response. Such interaction prevents upregulation of costimulatory molecules by APCs, hence decreasing the delivery of these signals to CD4+ T cells. These are the first data establishing that regulatory CD8+CD28– T cells occur in normal mice and play a critical role in disease resistance in CD28–/– animals.

Authors

Nader Najafian, Tanuja Chitnis, Alan D. Salama, Bing Zhu, Christina Benou, Xueli Yuan, Michael R. Clarkson, Mohamed H. Sayegh, Samia J. Khoury

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Figure 7

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CD8+CD28– T cell–induced suppression in vitro requires cell-cell contact...
CD8+CD28– T cell–induced suppression in vitro requires cell-cell contact and is APC dependent. MOG p35-55–specific IFN-γ–producing cells were measured by ELISPOT in cultures of CD8–/– on day 14 after immunization. (a) Addition of 100% purified CD8+CD28– T cells in a 2:1 ratio leads to complete suppression of IFN-γ spots only if in direct contact with responder cells (white bar), but not if separated by a Transwell membrane (black bar). Titration of the same number of CD28+/+ splenocytes as CD8+CD28– T cells only led to an increase of IFN-γ spots (dark gray bar). (b) CD8+CD28–, but not CD8+CD28+ cells originating from WT mice demonstrate similar suppressive activity in vitro because CD8+CD28– cells generated from CD28–/– mice as demonstrated. (c) Purified CD8+CD28– T cells are not able to suppress IFN-γ production by 100% purified CD4 T cells stimulated by PMA (10 ng/ml) and ionomycin (400 ng/ml). The coculture of CD8+CD28– and CD4+ cells results in accumulation of spots produced by each individual group of cells (black bar) after stimulation with PMA plus ionomycin. Con A is unable to stimulate purified CD4 cells in the absence of accessory cells. (d) Purified CD8+CD28– T cells added to cultures in 2:1 contact induce complete suppression of IFN-γ production by naive CD8–/– splenocytes stimulated by Con A at 5 μg/ml.