Regulatory functions of CD8+CD28– T cells in an autoimmune disease model
Nader Najafian, Tanuja Chitnis, Alan D. Salama, Bing Zhu, Christina Benou, Xueli Yuan, Michael R. Clarkson, Mohamed H. Sayegh, Samia J. Khoury
Nader Najafian, Tanuja Chitnis, Alan D. Salama, Bing Zhu, Christina Benou, Xueli Yuan, Michael R. Clarkson, Mohamed H. Sayegh, Samia J. Khoury
View: Text | PDF
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

×

Figure 7

Options: View larger image (or click on image) Download as PowerPoint
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.