Cutting edge: cell-extrinsic immune regulation by CTLA-4 expressed on conventional T cells |
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Authors: | Wang Chun Jing Kenefeck Rupert Wardzinski Lukasz Attridge Kesley Manzotti Claire Schmidt Emily M Qureshi Omar S Sansom David M Walker Lucy S K |
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Affiliation: | Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom. |
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Abstract: | The CTLA-4 pathway is a key regulator of T cell activation and a critical failsafe against autoimmunity. Although early models postulated that CTLA-4 transduced a negative signal, in vivo evidence suggests that CTLA-4 functions in a cell-extrinsic manner. That multiple cell-intrinsic mechanisms have been attributed to CTLA-4, yet its function in vivo appears to be cell-extrinsic, has been an ongoing paradox in the field. Although CTLA-4 expressed on conventional T cells (Tconv) can mediate inhibitory function, it is unclear why this fails to manifest as an intrinsic effect. In this study, we show that Tconv-expressed CTLA-4 can function in a cell-extrinsic manner in vivo. CTLA-4(+/+) T cells, from DO11/rag(-/-) mice that lack regulatory T cells, were able to regulate the response of CTLA-4(-/-) T cells in cotransfer experiments. This observation provides a potential resolution to the above paradox and suggests CTLA-4 function on both Tconv and regulatory T cells can be achieved through cell-extrinsic mechanisms. |
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