An obligate cell-intrinsic function for CD28 in Tregs
Open Access
- 2 January 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (2), 580-593
- https://doi.org/10.1172/jci65013
Abstract
Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3+ cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these “competitive” environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3+ Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.Keywords
This publication has 39 references indexed in Scilit:
- IL-2 Receptor Signaling Is Essential for the Development of Klrg1+ Terminally Differentiated T Regulatory CellsPublished by The American Association of Immunologists ,2012
- Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ TregsJCI Insight, 2012
- An N-Terminal Mutation of the Foxp3 Transcription Factor Alleviates Arthritis but Exacerbates DiabetesImmunity, 2012
- Loss of Epigenetic Modification Driven by the Foxp3 Transcription Factor Leads to Regulatory T Cell InsufficiencyImmunity, 2012
- Intrinsic and extrinsic control of peripheral T‐cell tolerance by costimulatory molecules of the CD28/ B7 familyImmunological Reviews, 2011
- The PD‐1 pathway in tolerance and autoimmunityImmunological Reviews, 2010
- Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in miceJCI Insight, 2010
- PD-L1 regulates the development, maintenance, and function of induced regulatory T cellsThe Journal of Experimental Medicine, 2009
- Regulatory T Cells Sequentially Migrate from Inflamed Tissues to Draining Lymph Nodes to Suppress the Alloimmune ResponseImmunity, 2009
- CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic toleranceThe Journal of Experimental Medicine, 2009